Science.gov

Sample records for receptor oxtr contributes

  1. The Oxytocin Receptor (OXTR) Contributes to Prosocial Fund Allocations in the Dictator Game and the Social Value Orientations Task

    PubMed Central

    Israel, Salomon; Lerer, Elad; Shalev, Idan; Uzefovsky, Florina; Riebold, Mathias; Laiba, Efrat; Bachner-Melman, Rachel; Maril, Anat; Bornstein, Gary; Knafo, Ariel; Ebstein, Richard P.

    2009-01-01

    Background Economic games observe social decision making in the laboratory that involves real money payoffs. Previously we have shown that allocation of funds in the Dictator Game (DG), a paradigm that illustrates costly altruistic behavior, is partially determined by promoter-region repeat region variants in the arginine vasopressin 1a receptor gene (AVPR1a). In the current investigation, the gene encoding the related oxytocin receptor (OXTR) was tested for association with the DG and a related paradigm, the Social Values Orientation (SVO) task. Methodology/Principal Findings Association (101 male and 102 female students) using a robust-family based test between 15 single tagging SNPs (htSNPs) across the OXTR was demonstrated with both the DG and SVO. Three htSNPs across the gene region showed significant association with both of the two games. The most significant association was observed with rs1042778 (p = 0.001). Haplotype analysis also showed significant associations for both DG and SVO. Following permutation test adjustment, significance was observed for 2–5 locus haplotypes (p<0.05). A second sample of 98 female subjects was subsequently and independently recruited to play the dictator game and was genotyped for the three significant SNPs found in the first sample. The rs1042778 SNP was shown to be significant for the second sample as well (p = 0.004, Fisher's exact test). Conclusions The demonstration that genetic polymorphisms for the OXTR are associated with human prosocial decision making converges with a large body of animal research showing that oxytocin is an important social hormone across vertebrates including Homo sapiens. Individual differences in prosocial behavior have been shown by twin studies to have a substantial genetic basis and the current investigation demonstrates that common variants in the oxytocin receptor gene, an important element of mammalian social circuitry, underlie such individual differences. PMID:19461999

  2. Generation of Oxtr cDNA(HA)-Ires-Cre Mice for Gene Expression in an Oxytocin Receptor Specific Manner.

    PubMed

    Hidema, Shizu; Fukuda, Tomokazu; Hiraoka, Yuichi; Mizukami, Hiroaki; Hayashi, Ryotaro; Otsuka, Ayano; Suzuki, Shingo; Miyazaki, Shinji; Nishimori, Katsuhiko

    2016-05-01

    The neurohypophysial hormone oxytocin (OXT) and its receptor (OXTR) have critical roles in the regulation of pro-social behaviors, including social recognition, pair bonding, parental behavior, and stress-related responses. Supporting this hypothesis, a portion of patients suffering from autism spectrum disorder have mutations, such as single nucleotide polymorphisms, or epigenetic modifications in their OXTR gene. We previously reported that OXTR-deficient mice exhibit pervasive social deficits, indicating the critical role of OXTR in social behaviors. In the present study, we generated Oxtr cDNA(HA)-Ires-Cre knock-in mice, expressing both OXTR and Cre recombinase under the control of the endogenous Oxtr promoter. Knock-in cassette of Oxtr cDNA(HA)-Ires-Cre consisted of Oxtr cDNA tagged with the hemagglutinin epitope at the 3' end (Oxtr cDNA(HA)), internal ribosomal entry site (Ires), and Cre. Cre was expressed in the uterus, mammary gland, kidney, and brain of Oxtr cDNA(HA)-Ires-Cre knock-in mice. Furthermore, the distribution of Cre in the brain was similar to that observed in Oxtr-Venus fluorescent protein expressing mice (Oxtr-Venus), another animal model previously generated by our group. Social behavior of Oxtr cDNA(HA)-Ires-Cre knock-in mice was similar to that of wild-type animals. We demonstrated that this construct is expressed in OXTR-expressing neurons specifically after an infection with the recombinant adeno-associated virus carrying the flip-excision switch vector. Using this system, we showed the transport of the wheat-germ agglutinin tracing molecule from the OXTR-expressing neurons to the innervated neurons in knock-in mice. This study might contribute to the monosynaptic analysis of neuronal circuits and to the optogenetic analysis of neurons expressing OXTR. PMID:26442453

  3. Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals

    PubMed Central

    Liu, Xiaoxi; Kawashima, Minae; Miyagawa, Taku; Otowa, Takeshi; Latt, Khun Zaw; Thiri, Myo; Nishida, Hisami; Sugiyama, Toshiro; Tsurusaki, Yoshinori; Matsumoto, Naomichi; Mabuchi, Akihiko; Tokunaga, Katsushi; Sasaki, Tsukasa

    2015-01-01

    The oxytocin receptor (OXTR) gene has been implicated as a risk gene for autism spectrum disorder (ASD)—a neurodevelopmental disorder with essential features of impairments in social communication and reciprocal interaction. The genetic associations between common variations in OXTR and ASD have been reported in multiple ethnic populations. However, little is known about the distribution of rare variations within OXTR in ASD patients. In this study, we resequenced the full length of OXTR in 105 ASD individuals using an approach that combined the power of next-generation sequencing technology, long-range PCR and DNA pooling. We demonstrated that rare variants with minor allele frequency as low as 0.05% could be reliably detected by our method. We identified 28 novel variants including potential functional variants in the intron region and one rare missense variant (R150S). We subsequently performed Sanger sequencing and validated five novel variants located in previously suggested candidate regions in ASD individuals. Further sequencing of 312 healthy subjects showed that the burden of rare variants is significantly higher in ASDs compared with healthy individuals. Our results support that the rare variation in OXTR gene might be involved in ASD. PMID:27081536

  4. No Association between Oxytocin Receptor (OXTR) Gene Polymorphisms and Experimentally Elicited Social Preferences

    PubMed Central

    Apicella, Coren L.; Cesarini, David; Johannesson, Magnus; Dawes, Christopher T.; Lichtenstein, Paul; Wallace, Björn; Beauchamp, Jonathan; Westberg, Lars

    2010-01-01

    Background Oxytocin (OXT) has been implicated in a suite of complex social behaviors including observed choices in economic laboratory experiments. However, actual studies of associations between oxytocin receptor (OXTR) gene variants and experimentally elicited social preferences are rare. Methodology/Principal Findings We test hypotheses of associations between social preferences, as measured by behavior in two economic games, and 9 single nucleotide polymorphisms (SNPs) of the OXTR gene in a sample of Swedish twins (n = 684). Two standard economic games, the dictator game and the trust game, both involving real monetary consequences, were used to elicit such preferences. After correction for multiple hypothesis testing, we found no significant associations between any of the 9 single nucleotide polymorphisms (SNPs) and behavior in either of the games. Conclusion We were unable to replicate the most significant association reported in previous research between the amount donated in a dictator game and an OXTR genetic variant. PMID:20585395

  5. Association between the oxytocin receptor (OXTR) gene and children's social cognition at 18 months.

    PubMed

    Wade, M; Hoffmann, T J; Wigg, K; Jenkins, J M

    2014-09-01

    At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation and self-recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social-cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, this study hypothesized that variability in the oxytocin receptor gene (OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socio-emotional functioning. At 18 months, social cognition was measured using previously validated and developmentally sensitive tasks assessing children's joint attention, empathy, cooperation and self-recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897 and rs237899. A family-based association design was used to control for population admixture and stratification, and additional non-genomic covariates were controlled. Results showed that variability in rs11131149 was significantly associated with social cognition (P=0.009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149-rs2254298 was also associated with social cognition (P=0.020). Implications for normative and pathological development are discussed, and key areas for future research are proposed. PMID:24916666

  6. Environmental stress, oxytocin receptor gene (OXTR) polymorphism, and mental health following collective stress.

    PubMed

    Lucas-Thompson, Rachel G; Holman, E Alison

    2013-04-01

    We examined whether the oxytocin receptor gene (OXTR) single nucleotide polymorphism (SNP) rs53576 genotype buffers the combined impact of negative social environments (e.g., interpersonal conflict/constraint) and economic stress on post-traumatic stress (PTS) symptoms and impaired daily functioning following collective stress (September 11th terrorist attacks). Saliva was collected by mail and used to genotype 704 respondents. Participants completed Web-based assessments of pre-9/11 mental health, acute stress 9-23 days after 9/11, the quality of social environments 1 year post-9/11, economic stress 18 months post-9/11, and PTS symptoms and impaired functioning 2 and 3 years post-9/11. Interactions between negative social environments and economic stress were examined separately based on OXTR rs53576 genotype (GG vs. any A allele). For individuals with an A allele, a negative social environment significantly increased PTS symptoms without regard to the level of economic stress experienced. However, for respondents with a GG genotype, negative social environments predicted elevated PTS symptoms only for those also experiencing high economic stress. Gender moderated associations between negative social environments, economic stress, and impaired functioning. The functioning of females was most affected by negative social environments regardless of genotype and economic stress, whereas the functioning of males was differentially susceptible to economic stress depending on OXTR genotype and negative social environments. These findings suggest that it is important to consider the combined impact of gender and ongoing stress in different domains as moderators of genetic vulnerability following collective stress. PMID:23470776

  7. Variation in the oxytocin receptor gene (OXTR) is associated with pair-bonding and social behavior

    PubMed Central

    Walum, Hasse; Lichtenstein, Paul; Neiderhiser, Jenae M.; Reiss, David; Ganiban, Jody M.; Spotts, Erica L.; Pedersen, Nancy L.; Anckarsäter, Henrik; Larsson, Henrik; Westberg, Lars

    2011-01-01

    Background In specific vole and primate species the neuropeptide Oxytocin (OT) plays a central role in the regulation of pair-bonding behavior. Here we investigate to what extent genetic variants in the oxytocin receptor gene (OXTR) are associated with pair-bonding and related social behaviors in humans. Methods We first genotyped twelve Single Nucleotide Polymorphisms (SNPs) in the Twin and Offspring Study in Sweden (TOSS, N=2309) and the Swedish Twin Study of CHild and Adolescent Development (TCHAD, N=1240) comprising measures of self-reported pair-bonding behavior. In the TOSS-sample we further investigated one the SNPs for measures of marital status and quality. Moreover, in the TCHAD sample we explored the longitudinal relationship between precursors of pair-bonding during childhood and subsequent behavior in romantic relationships. Finally, in TCHAD and in the Child and Adolescent Twin Study of Sweden (CATSS, N=1771) the association between the same SNP and childhood behaviors was investigated. Results One SNP (rs7632287) in OXTR was associated with traits reflecting pair-bonding in women in the TOSS and TCHAD samples. In girls the rs7632287 SNP was further associated with childhood social problems, which longitudinally predicted pair-bonding behavior in the TCHAD-sample. This association was replicated in the CATSS-sample in which an association between the same SNP and social interaction deficit symptoms from the autism spectrum was detected. Conclusion These results suggest an association between variation in OXTR and human pair-bonding and other social behaviors, possibly indicating that the well described influence of OT on affiliative behavior in voles could also be of importance for humans. PMID:22015110

  8. Cumulative risk on the oxytocin receptor gene (OXTR) underpins empathic communication difficulties at the first stages of romantic love.

    PubMed

    Schneiderman, Inna; Kanat-Maymon, Yaniv; Ebstein, Richard P; Feldman, Ruth

    2014-10-01

    Empathic communication between couples plays an important role in relationship quality and individual well-being and research has pointed to the role of oxytocin in providing the neurobiological substrate for pair-bonding and empathy. Here, we examined links between genetic variability on the oxytocin receptor gene (OXTR) and empathic behaviour at the initiation of romantic love. Allelic variations on five OXTR single nucleotide polymorphisms (SNPs) previously associated with susceptibility to disorders of social functioning were genotyped in 120 new lovers: OXTRrs13316193, rs2254298, rs1042778, rs2268494 and rs2268490. Cumulative genetic risk was computed by summing risk alleles on each SNP. Couples were observed in support-giving interaction and behaviour was coded for empathic communication, including affective congruence, maintaining focus on partner, acknowledging partner's distress, reciprocal exchange and non-verbal empathy. Hierarchical linear modelling indicated that individuals with high OXTR risk exhibited difficulties in empathic communication. OXTR risk predicted empathic difficulties above and beyond the couple level, relationship duration, and anxiety and depressive symptoms. Findings underscore the involvement of oxytocin in empathic behaviour during the early stages of social affiliation, and suggest the utility of cumulative risk and plasticity indices on the OXTR as potential biomarkers for research on disorders of social dysfunction and the neurobiology of empathy. PMID:23974948

  9. Association of Oxytocin Receptor Gene (OXTR) rs53576 Polymorphism with Sociality: A Meta-Analysis

    PubMed Central

    Li, Jingguang; Zhao, Yajun; Li, Rena; Broster, Lucas S.; Zhou, Chenglin; Yang, Suyong

    2015-01-01

    A common variant in the oxytocin receptor gene (OXTR), rs53576, has been broadly linked to socially related personality traits and behaviors. However, the pattern of published results is inconsistent. Here, we performed a meta-analysis to comprehensively evaluate the association. The literature was searched for relevant studies and effect sizes between individuals homozygous for the G allele (GG) and individuals with A allele carriers (AA/AG). Specifically, two indices of sociality were evaluated independently: i) general sociality (24 samples, n = 4955), i.e., how an individual responds to other people in general; and ii) close relationships (15 samples, n = 5262), i.e., how an individual responds to individuals with closed connections (parent-child or romantic relationship). We found positive association between the rs53576 polymorphism and general sociality (Cohen’s d = 0.11, p = .02); G allele homozygotes had higher general sociality than the A allele carriers. However, the meta-analyses did not detect significant genetic association between rs53576 and close relationships (Cohen’s d = 0.01, p = .64). In conclusion, genetic variation in the rs53576 influences general sociality, which further implies that it is worthy to systematically examine whether the rs53576 is a valid genetic marker for socially related psychiatric disorders. PMID:26121678

  10. Oxytocin Receptor Gene (OXTR) Polymorphism, Perceived Social Support, and Psychological Symptoms in Maltreated Adolescents

    PubMed Central

    Hostinar, Camelia E.; Cicchetti, Dante; Rogosch, Fred A.

    2014-01-01

    Despite the detrimental consequences of child maltreatment on developmental processes, some individuals show remarkable resilience, with few signs of psychopathology, while others succumb to dysfunction. Given that oxytocin has been shown to be involved in social affiliation, attachment, social support, trust, empathy, and other social or reproductive behaviors, we chose to examine the possible moderation of maltreatment effects on perceived social support and on psychological symptoms by a common SNP (rs53576) in the oxytocin receptor gene (OXTR). We studied adolescents (N = 425) aged approximately 13-15, including participants with objectively documented maltreatment histories (N = 263) and a non-maltreated comparison group from a comparable low-socioeconomic status background (N = 162). There was a significant genotype by maltreatment interaction such that maltreated adolescents with the G/G genotype perceived significantly lower social support compared to maltreated A-carriers, with no effect of genotype in the comparison group. Maltreated G/Gs also reported higher levels of Internalizing symptoms than A-carriers, even though they did not differ from them on objective measures of maltreatment (type, duration, or severity). G/G homozygotes may be more attuned to negative social experiences such as family maltreatment, while maltreated A-carriers were indistinguishable from non-maltreated adolescents in levels of mental health symptoms. PMID:24621832

  11. Religion priming and an oxytocin receptor gene (OXTR) polymorphism interact to affect self-control in a social context.

    PubMed

    Sasaki, Joni Y; Mojaverian, Taraneh; Kim, Heejung S

    2015-02-01

    Using a genetic moderation approach, this study examines how an experimental prime of religion impacts self-control in a social context, and whether this effect differs depending on the genotype of an oxytocin receptor gene (OXTR) polymorphism (rs53576). People with different genotypes of OXTR seem to have different genetic orientations toward sociality, which may have consequences for the way they respond to religious cues in the environment. In order to determine whether the influence of religion priming on self-control is socially motivated, we examine whether this effect is stronger for people who have OXTR genotypes that should be linked to greater rather than less social sensitivity (i.e., GG vs. AA/AG genotypes). The results showed that experimentally priming religion increased self-control behaviors for people with GG genotypes more so than people with AA/AG genotypes. Furthermore, this Gene × Religion interaction emerged in a social context, when people were interacting face to face with another person. This research integrates genetic moderation and social psychological approaches to address a novel question about religion's influence on self-control behavior, which has implications for coping with distress and psychopathology. These findings also highlight the importance of the social context for understanding genetic moderation of psychological effects. PMID:25640833

  12. Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition.

    PubMed

    Lerer, E; Levi, S; Salomon, S; Darvasi, A; Yirmiya, N; Ebstein, R P

    2008-10-01

    Evidence both from animal and human studies suggests that common polymorphisms in the oxytocin receptor (OXTR) gene are likely candidates to confer risk for autism spectrum disorders (ASD). In lower mammals, oxytocin is important in a wide range of social behaviors, and recent human studies have shown that administration of oxytocin modulates behavior in both clinical and non-clinical groups. Additionally, two linkage studies and two recent association investigations also underscore a possible role for the OXTR gene in predisposing to ASD. We undertook a comprehensive study of all 18 tagged SNPs across the entire OXTR gene region identified using HapMap data and the Haploview algorithm. Altogether 152 subjects diagnosed with ASDs (that is, DSM IV autistic disorder or pervasive developmental disorder--NOS) from 133 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED set of programs. Significant association with single SNPs and haplotypes (global P-values <0.05, following permutation test adjustment) were observed with ASD. Association was also observed with IQ and the Vineland Adaptive Behavior Scales (VABS). In particular, a five-locus haplotype block (rs237897-rs13316193-rs237889-rs2254298-rs2268494) was significantly associated with ASD (nominal global P=0.000019; adjusted global P=0.009) and a single haplotype (carried by 7% of the population) within that block showed highly significant association (P=0.00005). This is the third association study, in a third ethnic group, showing that SNPs and haplotypes in the OXTR gene confer risk for ASD. The current investigation also shows association with IQ and total VABS scores (as well as the communication, daily living skills and socialization subdomains), suggesting that this gene shapes both cognition and daily living skills that may cross diagnostic boundaries. PMID:17893705

  13. Rigorous tests of gene-environment interactions in a lab study of the oxytocin receptor gene (OXTR), alcohol exposure, and aggression.

    PubMed

    LoParo, Devon; Johansson, Ada; Walum, Hasse; Westberg, Lars; Santtila, Pekka; Waldman, Irwin

    2016-07-01

    Naturalistic studies of gene-environment interactions (G X E) have been plagued by several limitations, including difficulty isolating specific environmental risk factors from other correlated aspects of the environment, gene-environment correlation (rGE ), and the use of a single genetic variant to represent the influence of a gene. We present results from 235 Finnish young men in two lab studies of aggression and alcohol challenge that attempt to redress these limitations of the extant G X E literature. Specifically, we use a latent variable modeling approach in an attempt to more fully account for genetic variation across the oxytocin receptor gene (OXTR) and to robustly test its main effects on aggression and its interaction with alcohol exposure. We also modeled aggression as a latent variable comprising various indices, including the average and maximum levels of aggression, the earliest trial on which aggression was expressed, and the proportion of trials on which the minimum and maximum levels of aggression were expressed. The best fitting model for the genetic variation across OXTR included six factors derived from an exploratory factor analysis, roughly corresponding to six haplotype blocks. Aggression levels were higher on trials in which participants were administered alcohol, won, or were provoked. There was a significant main effect of OXTR on aggression across studies after controlling for covariates. The interaction of OXTR and alcohol was also significant across studies, such that OXTR had stronger effects on aggression in the alcohol administration condition. © 2015 Wiley Periodicals, Inc. PMID:26250573

  14. A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function

    PubMed Central

    Tost, Heike; Kolachana, Bhaskar; Hakimi, Shabnam; Lemaitre, Herve; Verchinski, Beth A.; Mattay, Venkata S.; Weinberger, Daniel R.; Meyer–Lindenberg, Andreas

    2010-01-01

    The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance. PMID:20647384

  15. The association between 2D:4D ratio and cognitive empathy is contingent on a common polymorphism in the oxytocin receptor gene (OXTR rs53576).

    PubMed

    Weisman, Omri; Pelphrey, Kevin A; Leckman, James F; Feldman, Ruth; Lu, Yunfeng; Chong, Anne; Chen, Ying; Monakhov, Mikhail; Chew, Soo Hong; Ebstein, Richard P

    2015-08-01

    Both testosterone and oxytocin influence an individual's accuracy in inferring another's feelings and emotions. Fetal testosterone, and the second-to-forth digit ratio (2D:4D) as its proxy, plays a role in social cognitive development, often by attenuating socio-affective skill. Conversely, oxytocin generally facilitates socio-affiliative and empathic cognition and behavior. A common polymorphism in the oxytocin receptor gene, OXTR rs53576, has been repeatedly linked with psychosocial competence, including empathy, with individuals homozygous for the G allele typically characterized by enhanced socio-cognitive skills compared to A allele carriers. We examined the role of oxytocin and testosterone in collectively contributing to individual differences in cognitive empathy as measured by Baron-Cohen's "Reading the Mind in the Eyes" task (RMET). Findings are based on a large cohort of male and female students (N=1463) of Han Chinese ethnicity. In line with existing literature, women outperformed men in the RMET. Men showed significantly lower 2D:4D ratio compared to women, indicating higher exposure to testosterone during the prenatal period. Interestingly, variation in the OXTR gene was found to interact with 2D:4D to predict men's (but not women's) RMET performance. Among men with GG allelic variation, those with low fetal testosterone performed better on the RMET, compared to men with GG and high fetal testosterone, suggesting greater identification of another's emotional state. Taken together, our data lend unique support to the mutual influence of the oxytocin and testosterone systems in shaping core aspect of human social cognition early in development, further suggesting that this effect is gender-specific. PMID:25935637

  16. The Oxytocin Receptor Gene (OXTR) in Relation to State Levels of Loneliness in Adolescence: Evidence for Micro-Level Gene-Environment Interactions

    PubMed Central

    van Roekel, Eeske; Verhagen, Maaike; Scholte, Ron H. J.; Kleinjan, Marloes; Goossens, Luc; Engels, Rutger C. M. E.

    2013-01-01

    Previous research has shown that the rs53576 variant of the oxytocin receptor gene (OXTR) is associated with trait levels of loneliness, but results are inconsistent. The aim of the present study is to examine micro-level effects of the OXTR rs53576 variant on state levels of loneliness in early adolescents. In addition, gene-environment interactions are examined between this OXTR variant and positive and negative perceptions of company. Data were collected in 278 adolescents (58% girls), by means of the Experience Sampling Method (ESM). Sampling periods consisted of six days with nine assessments per day. A relation was found between the OXTR rs53576 variant and state loneliness, in girls only. Girls carrying an A allele had higher levels of state loneliness than girls carrying the GG genotype. In addition, adolescents with an A allele were more affected by negative perceptions of company than GG carriers, on weekend days only. No significant gene-environment interactions were found with positive company. Adolescents carrying an A allele were more susceptible to negative environments during weekend days than GG carriers. Our findings emphasize the importance of operationalizing the phenotype and the environment accurately. PMID:24223720

  17. Gene-environment interaction between the oxytocin receptor (OXTR) gene and parenting behaviour on children's theory of mind.

    PubMed

    Wade, Mark; Hoffmann, Thomas J; Jenkins, Jennifer M

    2015-12-01

    Theory of mind (ToM) is the ability to interpret and understand human behaviour by representing the mental states of others. Like many human capacities, ToM is thought to develop through both complex biological and socialization mechanisms. However, no study has examined the joint effect of genetic and environmental influences on ToM. This study examined how variability in the oxytocin receptor gene (OXTR) and parenting behavior--two widely studied factors in ToM development-interacted to predict ToM in pre-school-aged children. Participants were 301 children who were part of an ongoing longitudinal birth cohort study. ToM was assessed at age 4.5 using a previously validated scale. Parenting was assessed through observations of mothers' cognitively sensitive behaviours. Using a family-based association design, it was suggestive that a particular variant (rs11131149) interacted with maternal cognitive sensitivity on children's ToM (P = 0.019). More copies of the major allele were associated with higher ToM as a function of increasing cognitive sensitivity. A sizeable 26% of the variability in ToM was accounted for by this interaction. This study provides the first empirical evidence of gene-environment interactions on ToM, supporting the notion that genetic factors may be modulated by potent environmental influences early in development. PMID:25977357

  18. A common oxytocin receptor gene (OXTR) polymorphism modulates intranasal oxytocin effects on the neural response to social cooperation in humans

    PubMed Central

    Feng, Chunliang; Lori, Adriana; Waldman, Irwin D.; Binder, Elisabeth B.; Haroon, Ebrahim; Rilling, James K.

    2015-01-01

    Intranasal oxytocin (OT) can modulate social-emotional functioning and related brain activity in humans. Consequently, OT has been discussed as a potential treatment for psychiatric disorders involving social behavioral deficits. However, OT effects are often heterogeneous across individuals. Here we explore individual differences in OT effects on the neural response to social cooperation as a function of the rs53576 polymorphism of the oxytocin receptor gene (OXTR). Previously, we conducted a double-blind, placebo-controlled study in which healthy men and women were randomized to treatment with intranasal OT or placebo. Afterwards, they were imaged with fMRI while playing an iterated Prisoner’s Dilemma Game with same-sex partners. Within the left ventral caudate nucleus, intranasal OT treatment increased activation to reciprocated cooperation in men, but tended to decrease activation in women. Here, we show that these sex differences in OT effects are specific to individuals with the rs53576 GG genotype, and are not found for other genotypes (rs53576 AA/AG). Thus, OT may increase the reward or salience of positive social interactions for male GG homozygotes, while decreasing those processes for female GG homozygotes. These results suggest that rs53576 genotype is an important variable to consider in future investigations of the clinical efficacy of intranasal OT treatment. PMID:26178189

  19. Genetic imaging of the association of oxytocin receptor gene (OXTR) polymorphisms with positive maternal parenting

    PubMed Central

    Michalska, Kalina J.; Decety, Jean; Liu, Chunyu; Chen, Qi; Martz, Meghan E.; Jacob, Suma; Hipwell, Alison E.; Lee, Steve S.; Chronis-Tuscano, Andrea; Waldman, Irwin D.; Lahey, Benjamin B.

    2013-01-01

    Background: Well-validated models of maternal behavior in small-brain mammals posit a central role of oxytocin in parenting, by reducing stress and enhancing the reward value of social interactions with offspring. In contrast, human studies are only beginning to gain insights into how oxytocin modulates maternal behavior and affiliation. Methods: To explore associations between oxytocin receptor genes and maternal parenting behavior in humans, we conducted a genetic imaging study of women selected to exhibit a wide range of observed parenting when their children were 4–6 years old. Results: In response to child stimuli during functional magnetic resonance imaging (fMRI), hemodynamic responses in brain regions that mediate affect, reward, and social behavior were significantly correlated with observed positive parenting. Furthermore, single nucleotide polymorphisms (SNPs) (rs53576 and rs1042778) in the gene encoding the oxytocin receptor were significantly associated with both positive parenting and hemodynamic responses to child stimuli in orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and hippocampus. Conclusions: These findings contribute to the emerging literature on the role of oxytocin in human social behavior and support the feasibility of tracing biological pathways from genes to neural regions to positive maternal parenting behaviors in humans using genetic imaging methods. PMID:24550797

  20. Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills

    PubMed Central

    Skuse, David H.; Lori, Adriana; Cubells, Joseph F.; Lee, Irene; Conneely, Karen N.; Puura, Kaija; Lehtimäki, Terho; Binder, Elisabeth B.; Young, Larry J.

    2014-01-01

    The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7–60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range −0.6 to −1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans. PMID:24367110

  1. DNA methylation and single nucleotide variants in the brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) genes are associated with anxiety/depression in older women

    PubMed Central

    Chagnon, Yvon C.; Potvin, Olivier; Hudon, Carol; Préville, Michel

    2015-01-01

    Background: Environmental effects and personal experiences could be expressed in individuals through epigenetic non-structural changes such as DNA methylation. This methylation could up- regulate or down-regulate corresponding gene expressions and modify related phenotypes. DNA methylation increases with aging and could be related to the late expression of some forms of mental disease. The objective of this study was to evaluate the association between anxiety disorders and/or depression in older women and DNA methylation for four genes related to anxiety or depression. Methods: Women aged 65 and older with (n = 19) or without (n = 24) anxiety disorders and/or major depressive episode (DSM-IV), were recruited. DNA methylation and single nucleotide variant (SNV) were evaluated from saliva, respectively by pyrosequencing and by PCR, for the following genes: brain-derived neurotrophic factor (BDNF; rs6265), oxytocin receptor (OXTR; rs53576), serotonin transporter (SLC6A4; rs25531), and apolipoprotein E (APOE; rs429358 and rs7412). Results: A greater BDNF DNA methylation was observed in subjects with anxiety/depression compared to control group subjects (Mean: 2.92 SD ± 0.74 vs. 2.34 ± 0.42; p= 0.0026). This difference was more pronounced in subjects carrying the BDNF rs6265 CT genotype (2.99 ± 0.41 vs. 2.27 ± 0.26; p= 0.0006) than those carrying the CC genotype (p= 0.0332); no subjects with the TT genotype were observed. For OXTR, a greater DNA methylation was observed in subjects with anxiety/depression, but only for those carrying the AA genotype of the OXTR rs53576 SNV, more particularly at one out of the seven CpGs studied (7.01 ± 0.94 vs. 4.44 ± 1.11; p= 0.0063). No significant differences were observed for APOE and SLC6A4. Conclusion: These results suggest that DNA methylation in interaction with SNV variations in BDNF and OXTR, are associated with the occurrence of anxiety/depression in older women. PMID:26175754

  2. Lack of Association between Oxytocin Receptor (OXTR) Gene Polymorphisms and Alexithymia: Evidence from Patients with Obsessive-Compulsive Disorder

    PubMed Central

    Koh, Min Jung; Kim, Wonji; Kang, Jee In; Namkoong, Kee; Kim, Se Joo

    2015-01-01

    Oxytocin receptor gene single nucleotide polymorphisms have been associated with structural and functional alterations in brain regions, which involve social-emotional processing. Therefore, oxytocin receptor gene polymorphisms may contribute to individual differences in alexithymia, which is considered to be a dysfunction of emotional processing. The aim of this study was to evaluate the association between oxytocin receptor gene single nucleotide polymorphisms or haplotypes and alexithymia in patients with obsessive-compulsive disorder. We recruited 355 patients with obsessive-compulsive disorder (234 men, 121 women). Alexithymia was measured by using the Toronto Alexithymia Scale. We performed single-marker and haplotype association analyses with eight single nucleotide polymorphisms (rs237885, rs237887, rs2268490, rs4686301, rs2254298, rs13316193, rs53576, and rs2268498) in the oxytocin receptor gene. There were no significant associations between any of the eight single nucleotide polymorphism of the oxytocin receptor gene and alexithymia. In addition, a six-locus haplotype block (rs237885-rs237887-rs2268490-rs4686301-rs2254298-rs13316193) was not significantly associated with alexithymia. These findings suggest that genetic variations in the oxytocin receptor gene may not explain a significant part of alexithymia in patients with obsessive-compulsive disorder. PMID:26599592

  3. Does the oxytocin receptor (OXTR) polymorphism (rs2254298) confer 'vulnerability' for psychopathology or 'differential susceptibility'? Insights from evolution.

    PubMed

    Brüne, Martin

    2012-01-01

    The diathesis-stress model of psychiatric conditions has recently been challenged by the view that it might be more accurate to speak of 'differential susceptibility' or 'plasticity' genes, rather than one-sidedly focusing on individual vulnerability. That is, the same allelic variation that predisposes to a psychiatric disorder if associated with (developmentally early) environmental adversity may lead to a better-than-average functional outcome in the same domain under thriving (or favourable) environmental conditions. Studies of polymorphic variations of the serotonin transporter gene, the monoamino-oxidase-inhibitor A coding gene or the dopamine D4 receptor gene indicate that the early environment plays a crucial role in the development of favourable versus unfavourable outcomes. Current evidence is limited, however, to establishing a link between genetic variation and behavioural phenotypes. In contrast, little is known about how plasticity may be expressed at the neuroanatomical level as a 'hard-wired' correlate of observable behaviour. The present review article seeks to further strengthen the argument in favour of the differential susceptibility theory by incorporating findings from behavioural and neuroanatomical studies in relation to genetic variation of the oxytocin receptor gene. It is suggested that polymorphic variation at the oxytocin receptor gene (rs2254298) is associated with sociability, amygdala volume and differential risk for psychiatric conditions including autism, depression and anxiety disorder, depending on the quality of early environmental experiences. Seeing genetic variation at the core of developmental plasticity can explain, in contrast to the diathesis-stress perspective, why evolution by natural selection has maintained such 'risk' alleles in the gene pool of a population. PMID:22510359

  4. Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder.

    PubMed

    Parker, Karen J; Garner, Joseph P; Libove, Robin A; Hyde, Shellie A; Hornbeak, Kirsten B; Carson, Dean S; Liao, Chun-Ping; Phillips, Jennifer M; Hallmayer, Joachim F; Hardan, Antonio Y

    2014-08-19

    The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD. PMID:25092315

  5. The oxytocin receptor gene (OXTR) localizes to human chromosome 3p25 by fluorescence in situ hybridization and PCR analysis of somatic cell hybrids

    SciTech Connect

    Simmons, C.F. Jr.; Clancy, T.E.; Quan, R.

    1995-04-10

    The human oxytocin receptor regulates parturition and myometrial contractility, breast milk let-down, and reproductive behaviors in the mammalian central nervous system. Kimura et al. recently identified a human oxytocin receptor cDNA by means of expression cloning from a human myometrial cDNA library. To elucidate further the molecular mechanisms that regulate oxytocin receptor gene expression and to define the expected Mendelian inheritance of possible human disease states, we must determine the number of genes, their localization, and their organization and structure. We summarize below our data indicating that the human oxytocin receptor gene is localized to 3p25 and exists as a single copy in the haploid genome. 9 refs., 2 figs.

  6. Evolutionary pattern in the OXT-OXTR system in primates: Coevolution and positive selection footprints

    PubMed Central

    Vargas-Pinilla, Pedro; Paré, Pamela; Tovo-Rodrigues, Luciana; Vieira, Carlos Meton de Alencar Gadelha; Xavier, Agatha; Comas, David; Pissinatti, Alcides; Sinigaglia, Marialva; Rigo, Maurício Menegatti; Vieira, Gustavo Fioravanti; Lucion, Aldo B.; Salzano, Francisco Mauro; Bortolini, Maria Cátira

    2015-01-01

    Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system. PMID:25535371

  7. Evolutionary pattern in the OXT-OXTR system in primates: coevolution and positive selection footprints.

    PubMed

    Vargas-Pinilla, Pedro; Paixão-Côrtes, Vanessa Rodrigues; Paré, Pamela; Tovo-Rodrigues, Luciana; Vieira, Carlos Meton de Alencar Gadelha; Xavier, Agatha; Comas, David; Pissinatti, Alcides; Sinigaglia, Marialva; Rigo, Maurício Menegatti; Vieira, Gustavo Fioravanti; Lucion, Aldo B; Salzano, Francisco Mauro; Bortolini, Maria Cátira

    2015-01-01

    Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system. PMID:25535371

  8. NMDA receptor contributions to visual contrast coding

    PubMed Central

    Manookin, Michael B.; Weick, Michael; Stafford, Benjamin K.; Demb, Jonathan B.

    2010-01-01

    Summary In the retina, it is not well understood how visual processing depends on AMPA- and NMDA-type glutamate receptors. Here, we investigated how these receptors contribute to contrast coding in identified guinea pig ganglion cell types, in vitro. NMDA-mediated responses were negligible in ON α cells but substantial in OFF α and δ cells. OFF δ cell NMDA receptors were composed of GluN2B subunits. Using a novel deconvolution method, we determined the individual contributions of AMPA, NMDA and inhibitory currents to light responses of each cell type. OFF α and δ cells used NMDA receptors for encoding either the full contrast range (α), including near-threshold responses, or only a high range (δ). However, contrast sensitivity depended substantially on NMDA receptors only in OFF α cells. NMDA receptors contribute to visual contrast coding in a cell-type specific manner. Certain cell types generate excitatory responses using primarily AMPA receptors or disinhibition. PMID:20670835

  9. Role of the Oxytocin Receptor Expressed in the Rostral Medullary Raphe in Thermoregulation During Cold Conditions.

    PubMed

    Kasahara, Yoshiyuki; Tateishi, Yuko; Hiraoka, Yuichi; Otsuka, Ayano; Mizukami, Hiroaki; Ozawa, Keiya; Sato, Keisuke; Hidema, Shizu; Nishimori, Katsuhiko

    2015-01-01

    Recent papers have reported that oxytocin (Oxt) and the oxytocin receptor (Oxtr) may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient (Oxtr (-/-)) mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR), the brain region known to control thermogenesis in brown adipose tissue (BAT). Through immunohistochemistry, we detected neurons expressing Oxtr and c-Fos in the RMR of mice exposed to cold conditions. Up to 40% of Oxtr-positive neurons in RMR were classified as glutamatergic neurons, as shown by immunostaining using anti-VGLUT3 antibody. In addition, mice with exclusive expression of Oxtr in the RMR were generated by injecting an AAV-Oxtr vector into the RMR region of Oxtr (-/-) mice. We confirmed the recovery of thermoregulatory ability in the manipulated mice during exposure to cold conditions. Moreover, mice with RMR-specific expression of Oxtr lost the typical morphological change in BAT observed in Oxtr (-/-) mice. Additionally, increased expression of the β3-adrenergic receptor gene, Adrb3, was observed in BAT. These results are the first to show the critical role of RMR Oxtr expression in thermoregulation during cold conditions. PMID:26635729

  10. OXTR polymorphism predicts social relationships through its effects on social temperament.

    PubMed

    Creswell, Kasey G; Wright, Aidan G C; Troxel, Wendy M; Ferrell, Robert E; Flory, Janine D; Manuck, Stephen B

    2015-06-01

    Humans have a fundamental need for strong interpersonal bonds, yet individuals differ appreciably in their degree of social integration. That these differences are also substantially heritable has spurred interest in biological mechanisms underlying the quality and quantity of individuals' social relationships. We propose that polymorphic variation in the oxytocin receptor gene (OXTR) associates with complex social behaviors and social network composition through intermediate effects on negative affectivity and the psychological processing of socially relevant information. We tested a hypothesized social cascade from the molecular level (OXTR variation) to the social environment, through negative affectivity and inhibited sociality, in a sample of 1295 men and women of European American (N = 1081) and African American (N = 214) ancestry. Compared to European Americans having any T allele of rs1042778, individuals homozygous for the alternate G allele reported significantly lower levels of negative affectivity and inhibited sociality, which in turn predicted significantly higher levels of social support and a larger/more diverse social network. Moreover, the effect of rs1042778 variation on social support was fully accounted for by associated differences in negative affectivity and inhibited sociality. Results replicated in the African American sample. Findings suggest that OXTR variation modulates levels of social support via proximal impacts on individual temperament. PMID:25326040

  11. OXTR polymorphism predicts social relationships through its effects on social temperament

    PubMed Central

    Wright, Aidan G. C.; Troxel, Wendy M.; Ferrell, Robert E.; Flory, Janine D.; Manuck, Stephen B.

    2015-01-01

    Humans have a fundamental need for strong interpersonal bonds, yet individuals differ appreciably in their degree of social integration. That these differences are also substantially heritable has spurred interest in biological mechanisms underlying the quality and quantity of individuals’ social relationships. We propose that polymorphic variation in the oxytocin receptor gene (OXTR) associates with complex social behaviors and social network composition through intermediate effects on negative affectivity and the psychological processing of socially relevant information. We tested a hypothesized social cascade from the molecular level (OXTR variation) to the social environment, through negative affectivity and inhibited sociality, in a sample of 1295 men and women of European American (N = 1081) and African American (N = 214) ancestry. Compared to European Americans having any T allele of rs1042778, individuals homozygous for the alternate G allele reported significantly lower levels of negative affectivity and inhibited sociality, which in turn predicted significantly higher levels of social support and a larger/more diverse social network. Moreover, the effect of rs1042778 variation on social support was fully accounted for by associated differences in negative affectivity and inhibited sociality. Results replicated in the African American sample. Findings suggest that OXTR variation modulates levels of social support via proximal impacts on individual temperament. PMID:25326040

  12. Nucleus accumbens lentiviral-mediated gain of function of the oxytocin receptor regulates anxiety- and ethanol-related behaviors in adult mice.

    PubMed

    Bahi, Amine; Al Mansouri, Shamma; Al Maamari, Elyazia

    2016-10-01

    Anxiety is believed to influence ethanol use human in alcoholics. Studies using laboratory animals suggested an interaction between oxytocin and the behavioral effects of ethanol. Our previous study implicated a potential role for the oxytocin receptor (OxtR) in regulating ethanol-conditioned place preference. Here, we examined anxiety and the behavioral responses to ethanol in C57BL/6 mice stereotaxically injected in the nucleus accumbens (NAcc) with lentiviral vectors expressing an empty vector (Mock) or the OxtR cDNA. For anxiety we used the elevated-plus maze, the open-field and the marble-burying tests and for ethanol we used the two-bottle choice paradigm, the wire-hanging and ethanol-induced loss-of-righting-reflex tests. We found that, compared to Mock, OxtR overexpression led to anxiolytic-like behavior without altering spontaneous locomotor activity. Most importantly, we found that, relative to Mock controls, increased expression of the OxtR in the NAcc led to decreased ethanol consumption and preference in the two-bottle choice protocol and increased resistance to ethanol-induced sedation. We also compared the consequence of OxtR modulation on the consumption and preference of saccharin and quinine and found that the two experimental groups did not differ for any tastant. These results provide further evidence that the oxytocin system contributes to the regulation of ethanol drinking and sensitivity and position OxtR as a central molecular mediator of ethanol's effects within the mesolimbic system. Taken together, the current findings suggest that OxtR manipulation may be a relevant strategy to address ethanol use disorders. PMID:27306084

  13. Are age and sex differences in brain oxytocin receptors related to maternal and infanticidal behavior in naïve mice?

    PubMed

    Olazábal, Daniel E; Alsina-Llanes, Marcela

    2016-01-01

    This article is part of a Special Issue "Parental Care". There is significant variability in the behavioral responses displayed by naïve young and adult mice when first exposed to pups. This variability has been associated with differences in the expression of oxytocin receptors (OXTRs) in the brain in several species. Experiment I investigated the behavioral responses of juvenile, adolescent, and adult CB57BL/6 males and females when first exposed to pups. We found an age increase in maternal females (11% of juveniles, 20% of adolescents, and 50% of young adults), and infanticidal males (0% of juveniles, 30% of adolescents, 44.5% of young adults, and 100% of older adults). Experiment II investigated OXTR density in the brain of juvenile and adult mice. Our results revealed an age decline in the density of OXTR in several brain regions, including the lateral septum, cingulated and posterior paraventricular thalamic nucleus in both males and females. Adult females had higher OXTR density in the ventromedial nucleus/postero-ventral hypothalamus (VMH) and the accessory olfactory bulb (AOB), but lower density in the ventral region of the lateral septum (LSv) than juveniles. Males had lower OXTR density in the anterior olfactory area (AOA) compared to juveniles. No age or sex differences were found in the medial preoptic area, and amygdaloid nuclei, among other brain regions. This study suggests that 1) maturation of parental and infanticidal behavioral responses is not reached until adulthood; 2) the pattern of development of OXTR in the mouse brain is unique, region specific, and differs from that observed in other rodents; 3) either up or down regulation of OXTR in a few brain regions (VMH/AOB/LSv/AOA) might contribute to age or sex differences in parental or infanticidal behavior. PMID:25910577

  14. Normal Maternal Behavior, But Increased Pup Mortality, in Conditional Oxytocin Receptor Knockout Females

    PubMed Central

    Macbeth, Abbe H.; Stepp, Jennifer E.; Lee, Heon-Jin; Young, W. Scott; Caldwell, Heather K.

    2011-01-01

    Oxytocin (Oxt) and the Oxt receptor (Oxtr) are implicated in the onset of maternal behavior in a variety of species. Recently, we developed two Oxtr knockout lines: a total body knockout (Oxtr−/−) and a conditional Oxtr knockout (OxtrFB/FB) in which the Oxtr is lacking only in regions of the forebrain, allowing knockout females to potentially nurse and care for their biological offspring. In the current study, we assessed maternal behavior of postpartum OxtrFB/FB females toward their own pups and maternal behavior of virgin Oxtr−/− females toward foster pups and compared knockouts of both lines to wildtype (Oxtr+/+) littermates. We found that both Oxtr−/− and OxtrFB/FB females appear to have largely normal maternal behaviors. However, with first litters, approximately 40% of the OxtrFB/FB knockout dams experienced high pup mortality, compared to fewer than 10% of the Oxtr+/+ dams. We then went on to test whether or not this phenotype occurred in subsequent litters or when the dams were exposed to an environmental disturbance. We found that regardless of the degree of external disturbance, OxtrFB/FB females lost more pups on their first and second litters compared to wildtype females. Possible reasons for higher pup mortality in OxtrFB/FB females are discussed. PMID:20939667

  15. Differential Susceptibility in Spillover Between Interparental Conflict and Maternal Parenting Practices: Evidence for OXTR and 5-HTT Genes

    PubMed Central

    Sturge-Apple, Melissa L.; Cicchetti, Dante; Davies, Patrick T.; Suor, Jennifer H.

    2012-01-01

    Guided by the affective spillover hypothesis and the differential susceptibility to environmental influence frameworks, the present study examined how associations between interparental conflict and mothers’ parenting practices were moderated by serotonin transporter (5-HTT) and oxytocin receptor (OXTR) genes. A sample of 201 mothers and their two-year old child participated in a laboratory-based research assessment. Results supported differential susceptibility hypotheses within spillover frameworks. With respect to OXTR rs53576, mothers with the GG genotype showed greater differential maternal sensitivity across varying levels of interparental conflict. Mothers with one or two copies of the 5-HTTLPR S allele demonstrated differential susceptibility for both sensitive and harsh/punitive caregiving behaviors. Finally, analyses examined whether maternal depressive symptoms and emotional closeness to their child mediated the moderating effects. Findings suggest that maternal emotional closeness with their child indirectly linked OXTR with maternal sensitivity. The results highlight how molecular genetics may explain heterogeneity in spillover models with differential implications for specific parenting behaviors. Implications for clinicians and therapists working with maritally distressed parents are discussed. PMID:22563705

  16. Type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although the alpha 7 nicotinic receptor exerts anti-inflammatory effects on immune cells, the role of muscarinic receptors in mucosal homeostasis, response to enteric pathogens, and modulation of immune cell function is undefined. The contribution of type 3 muscarinic receptor (M3R) to mucosal homeo...

  17. Role of the Oxytocin Receptor Expressed in the Rostral Medullary Raphe in Thermoregulation During Cold Conditions

    PubMed Central

    Kasahara, Yoshiyuki; Tateishi, Yuko; Hiraoka, Yuichi; Otsuka, Ayano; Mizukami, Hiroaki; Ozawa, Keiya; Sato, Keisuke; Hidema, Shizu; Nishimori, Katsuhiko

    2015-01-01

    Recent papers have reported that oxytocin (Oxt) and the oxytocin receptor (Oxtr) may be involved in the regulation of food intake in mammals. We therefore suspected the Oxt/Oxtr system to be involved in energy homeostasis. In previous studies, we found a tendency toward obesity in Oxtr-deficient (Oxtr−/−) mice, as well as impaired thermoregulation when these mice were exposed to cold conditions. In the present study, we observed the expression of Oxtr in the rostral medullary raphe (RMR), the brain region known to control thermogenesis in brown adipose tissue (BAT). Through immunohistochemistry, we detected neurons expressing Oxtr and c-Fos in the RMR of mice exposed to cold conditions. Up to 40% of Oxtr-positive neurons in RMR were classified as glutamatergic neurons, as shown by immunostaining using anti-VGLUT3 antibody. In addition, mice with exclusive expression of Oxtr in the RMR were generated by injecting an AAV-Oxtr vector into the RMR region of Oxtr−/− mice. We confirmed the recovery of thermoregulatory ability in the manipulated mice during exposure to cold conditions. Moreover, mice with RMR-specific expression of Oxtr lost the typical morphological change in BAT observed in Oxtr−/− mice. Additionally, increased expression of the β3-adrenergic receptor gene, Adrb3, was observed in BAT. These results are the first to show the critical role of RMR Oxtr expression in thermoregulation during cold conditions. PMID:26635729

  18. The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2.

    PubMed

    Leonzino, Marianna; Busnelli, Marta; Antonucci, Flavia; Verderio, Claudia; Mazzanti, Michele; Chini, Bice

    2016-04-01

    Oxytocin and its receptor (Oxtr) play a crucial role in the postnatal transition of neuronal GABA neurotransmission from excitatory to inhibitory, a developmental process known as the GABA switch. Using hippocampal neurons from Oxtr-null mice, we show that (1) Oxtr is necessary for the correct timing of the GABA switch by upregulating activity of the chloride cotransporter KCC2, (2) Oxtr, in a very early and narrow time window, directly modulates the functional activity of KCC2 by promoting its phosphorylation and insertion/stabilization at the neuronal surface, and (3) in the absence of Oxtr, electrophysiological alterations are recorded in mature neurons, a finding consistent with a reduced level of KCC2 and increased susceptibility to seizures observed in adult Oxtr-null mice. These data identify KCC2 as a key target of oxytocin in postnatal events that may be linked to pathogenesis of neurodevelopmental disorders. PMID:27052180

  19. The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2

    PubMed Central

    Leonzino, Marianna; Busnelli, Marta; Antonucci, Flavia; Verderio, Claudia; Mazzanti, Michele; Chini, Bice

    2016-01-01

    Summary Oxytocin and its receptor (Oxtr) play a crucial role in the postnatal transition of neuronal GABA neurotransmission from excitatory to inhibitory, a developmental process known as the GABA switch. Using hippocampal neurons from Oxtr-null mice, we show that (1) Oxtr is necessary for the correct timing of the GABA switch by upregulating activity of the chloride cotransporter KCC2, (2) Oxtr, in a very early and narrow time window, directly modulates the functional activity of KCC2 by promoting its phosphorylation and insertion/stabilization at the neuronal surface, and (3) in the absence of Oxtr, electrophysiological alterations are recorded in mature neurons, a finding consistent with a reduced level of KCC2 and increased susceptibility to seizures observed in adult Oxtr-null mice. These data identify KCC2 as a key target of oxytocin in postnatal events that may be linked to pathogenesis of neurodevelopmental disorders. PMID:27052180

  20. Interaction between oxytocin receptor DNA methylation and genotype is associated with risk of postpartum depression in women without depression in pregnancy

    PubMed Central

    Bell, Aleeca F.; Carter, C. S.; Steer, Colin D.; Golding, Jean; Davis, John M.; Steffen, Alana D.; Rubin, Leah H.; Lillard, Travis S.; Gregory, Steven P.; Harris, James C.; Connelly, Jessica J.

    2015-01-01

    Postpartum depression (PPD) affects up to 19% of women, negatively impacting maternal and infant health. Reductions in plasma oxytocin levels have been associated with PPD and heritability studies have established a genetic contribution. Epigenetic regulation of the oxytocin receptor gene (OXTR) has been demonstrated and we hypothesized that individual epigenetic variability at OXTR may impact the development of PPD and that such variability may be central to predicting risk. This case-control study is nested within the Avon Longitudinal Study of Parents and Children and included 269 cases with PPD and 276 controls matched on age group, parity, and presence or absence of depressive symptoms in pregnancy as assessed by the Edinburgh Postnatal Depression Scale. OXTR DNA methylation (CpG site -934) and genotype (rs53576 and rs2254298) were assayed from DNA extracted from blood collected during pregnancy. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of elevated symptoms of PPD with genotype, methylation, and their interaction adjusted for psychosocial factors (n = 500). There was evidence of an interaction between rs53576 and methylation in the OXTR gene amongst women who did not have depression prenatally but developed PPD (p interaction = 0.026, adjusted for covariates, n = 257). Those women with GG genotype showed 2.63 greater odds of PPD for every 10% increase in methylation level (95% CI: 1.37, 5.03), whereas methylation was unrelated to PPD amongst “A” carriers (OR = 1.00, 95% CI: 0.58, 1.73). There was no such interaction among women with PPD and prenatal depression. These data indicate that epigenetic variation that decreases expression of OXTR in a susceptible genotype may play a contributory role in the etiology of PPD. PMID:26257770

  1. RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles

    PubMed Central

    Keebaugh, Alaine C.; Barrett, Catherine E.; LaPrairie, Jamie L.; Jenkins, Jasmine J.; Young, Larry J.

    2015-01-01

    Oxytocin modulates many aspects of social cognition and behaviors, including maternal nurturing, social recognition and bonding. Natural variation in oxytocin receptor (OXTR) density in the nucleus accumbens (NAcc) is associated with variation in alloparental behavior, and artificially enhancing OXTR expression in the NAcc enhances alloparental behavior and pair bonding in socially monogamous prairie voles. Furthermore, infusion of an OXTR antagonist into the nucleus accumbens (NAcc) inhibits alloparental behavior and partner preference formation. However, antagonists can promiscuously interact with other neuropeptide receptors. To directly examine the role of OXTR signaling in social bonding, we used RNA interference to selectively knockdown, but not eliminate, OXTR in the NAcc of female prairie voles and examined the impact on social behaviors. Using an adeno-associated viral vector expressing a short hairpin RNA (shRNA) targeting Oxtr mRNA, we reduced accumbal OXTR density in female prairie voles from juvenile age through adulthood. Females receiving the shRNA vector displayed a significant reduction in alloparental behavior and disrupted partner preference formation. These are the first direct demonstrations that OXTR plays a critical role in alloparental behavior and adult social attachment, and suggest that natural variation in OXTR expression in this region alone can create variation in social behavior. PMID:25874849

  2. Polymorphisms of the OXTR gene explain why sales professionals love to help customers

    PubMed Central

    Verbeke, Willem; Bagozzi, Richard P.; van den Berg, Wouter E.; Lemmens, Aurelie

    2013-01-01

    Polymorphisms of the OXTR gene affect people's social interaction styles in various social encounters: carriers of the OXTR GG, compared to the OXTR AA/AG in general, are more motivated to interact socially and detect social salience. We focus on sales professionals operating in knowledge intensive organizations. Study 1, with a sample of 141 sales people, shows that carriers of the OXTR GG allele, compared to the OXTR AA/AG allele, are more motivated to help customers than to manipulatively impose goods/services on them. Study 2, using genomic functional magnetic resonance imaging (fMRI) on a sample of 21 sales professionals processing facial pictures with different emotional valences, investigates key nuclei of social brain regions (SBRs). Compared to OXTR AA/AG carriers, OXTR GG carriers experience greater effective connectivity between SBRs of interest measured by Granger causality tests using univariate Haugh tests. In addition, the multivariate El-Himdi and Roy tests demonstrate that the amygdala, prefrontal cortex, and pars opercularis (inferior frontal gyrus) play key roles when processing emotional expressions. The bilateral amygdala and medial prefrontal cortex (mPFC) show significantly greater clout—influence on other brain regions—for GG allele carriers than non-carriers; likewise, the bilateral pars opercularis, left amygdala, and left mPFC are more receptive to activity in other brain regions among GG allele carriers than AG/AA allele carriers are. Thus, carriers of the OXTR GG allele are more sensitive to changes in emotional cues, enhancing social salience. To our knowledge, this is the first study on how insights from imaging genetics help understanding of the social motivation of people operating in a professional setting. PMID:24348351

  3. Polymorphisms of the OXTR gene explain why sales professionals love to help customers.

    PubMed

    Verbeke, Willem; Bagozzi, Richard P; van den Berg, Wouter E; Lemmens, Aurelie

    2013-01-01

    Polymorphisms of the OXTR gene affect people's social interaction styles in various social encounters: carriers of the OXTR GG, compared to the OXTR AA/AG in general, are more motivated to interact socially and detect social salience. We focus on sales professionals operating in knowledge intensive organizations. Study 1, with a sample of 141 sales people, shows that carriers of the OXTR GG allele, compared to the OXTR AA/AG allele, are more motivated to help customers than to manipulatively impose goods/services on them. Study 2, using genomic functional magnetic resonance imaging (fMRI) on a sample of 21 sales professionals processing facial pictures with different emotional valences, investigates key nuclei of social brain regions (SBRs). Compared to OXTR AA/AG carriers, OXTR GG carriers experience greater effective connectivity between SBRs of interest measured by Granger causality tests using univariate Haugh tests. In addition, the multivariate El-Himdi and Roy tests demonstrate that the amygdala, prefrontal cortex, and pars opercularis (inferior frontal gyrus) play key roles when processing emotional expressions. The bilateral amygdala and medial prefrontal cortex (mPFC) show significantly greater clout-influence on other brain regions-for GG allele carriers than non-carriers; likewise, the bilateral pars opercularis, left amygdala, and left mPFC are more receptive to activity in other brain regions among GG allele carriers than AG/AA allele carriers are. Thus, carriers of the OXTR GG allele are more sensitive to changes in emotional cues, enhancing social salience. To our knowledge, this is the first study on how insights from imaging genetics help understanding of the social motivation of people operating in a professional setting. PMID:24348351

  4. Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with emotional and cognitive empathy.

    PubMed

    Uzefovsky, F; Shalev, I; Israel, S; Edelman, S; Raz, Y; Mankuta, D; Knafo-Noam, A; Ebstein, R P

    2015-01-01

    Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine vasopressin receptor 1a (AVPR1a) genes contribute to social cognition in both animals and humans and hence are prominent candidates for contributing to empathy. The following research examined the associations between polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the two genes and measures of empathy. The current findings contribute to our understanding of the distinct neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of both oxytocin and vasopressin in modulating human emotions. PMID:25476609

  5. Muscarinic ACh Receptors Contribute to Aversive Olfactory Learning in Drosophila

    PubMed Central

    Silva, Bryon; Molina-Fernández, Claudia; Ugalde, María Beatriz; Tognarelli, Eduardo I.; Angel, Cristian; Campusano, Jorge M.

    2015-01-01

    The most studied form of associative learning in Drosophila consists in pairing an odorant, the conditioned stimulus (CS), with an unconditioned stimulus (US). The timely arrival of the CS and US information to a specific Drosophila brain association region, the mushroom bodies (MB), can induce new olfactory memories. Thus, the MB is considered a coincidence detector. It has been shown that olfactory information is conveyed to the MB through cholinergic inputs that activate acetylcholine (ACh) receptors, while the US is encoded by biogenic amine (BA) systems. In recent years, we have advanced our understanding on the specific neural BA pathways and receptors involved in olfactory learning and memory. However, little information exists on the contribution of cholinergic receptors to this process. Here we evaluate for the first time the proposition that, as in mammals, muscarinic ACh receptors (mAChRs) contribute to memory formation in Drosophila. Our results show that pharmacological and genetic blockade of mAChRs in MB disrupts olfactory aversive memory in larvae. This effect is not explained by an alteration in the ability of animals to respond to odorants or to execute motor programs. These results show that mAChRs in MB contribute to generating olfactory memories in Drosophila. PMID:26380118

  6. Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens

    PubMed Central

    Halberstadt, Adam L.; Geyer, Mark A.

    2011-01-01

    Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT2 receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT2A receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT2 and non-5-HT2 receptors. PMID:21256140

  7. Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens.

    PubMed

    Halberstadt, Adam L; Geyer, Mark A

    2011-09-01

    Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT(2) receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT(2A) receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT(2) and non-5-HT(2) receptors. PMID:21256140

  8. Vestibular receptors contribute to cortical auditory evoked potentials☆

    PubMed Central

    Todd, Neil P.M.; Paillard, Aurore C.; Kluk, Karolina; Whittle, Elizabeth; Colebatch, James G.

    2014-01-01

    Acoustic sensitivity of the vestibular apparatus is well-established, but the contribution of vestibular receptors to the late auditory evoked potentials of cortical origin is unknown. Evoked potentials from 500 Hz tone pips were recorded using 70 channel EEG at several intensities below and above the vestibular acoustic threshold, as determined by vestibular evoked myogenic potentials (VEMPs). In healthy subjects both auditory mid- and long-latency auditory evoked potentials (AEPs), consisting of Na, Pa, N1 and P2 waves, were observed in the sub-threshold conditions. However, in passing through the vestibular threshold, systematic changes were observed in the morphology of the potentials and in the intensity dependence of their amplitude and latency. These changes were absent in a patient without functioning vestibular receptors. In particular, for the healthy subjects there was a fronto-central negativity, which appeared at about 42 ms, referred to as an N42, prior to the AEP N1. Source analysis of both the N42 and N1 indicated involvement of cingulate cortex, as well as bilateral superior temporal cortex. Our findings are best explained by vestibular receptors contributing to what were hitherto considered as purely auditory evoked potentials and in addition tentatively identify a new component that appears to be primarily of vestibular origin. PMID:24321822

  9. Does the kappa opioid receptor system contribute to pain aversion?

    PubMed Central

    Cahill, Catherine M.; Taylor, Anna M. W.; Cook, Christopher; Ong, Edmund; Morón, Jose A.; Evans, Christopher J.

    2014-01-01

    The kappa opioid receptor (KOR) and the endogenous peptide-ligand dynorphin have received significant attention due the involvement in mediating a variety of behavioral and neurophysiological responses, including opposing the rewarding properties of drugs of abuse including opioids. Accumulating evidence indicates this system is involved in regulating states of motivation and emotion. Acute activation of the KOR produces an increase in motivational behavior to escape a threat, however, KOR activation associated with chronic stress leads to the expression of symptoms indicative of mood disorders. It is well accepted that KOR can produce analgesia and is engaged in chronic pain states including neuropathic pain. Spinal studies have revealed KOR-induced analgesia in reversing pain hypersensitivities associated with peripheral nerve injury. While systemic administration of KOR agonists attenuates nociceptive sensory transmission, this effect appears to be a stress-induced effect as anxiolytic agents, including delta opioid receptor agonists, mitigate KOR agonist-induced analgesia. Additionally, while the role of KOR and dynorphin in driving the dysphoric and aversive components of stress and drug withdrawal has been well characterized, how this system mediates the negative emotional states associated with chronic pain is relatively unexplored. This review provides evidence that dynorphin and the KOR system contribute to the negative affective component of pain and that this receptor system likely contributes to the high comorbidity of mood disorders associated with chronic neuropathic pain. PMID:25452729

  10. A Conditional Knockout Mouse Line of the Oxytocin Receptor

    PubMed Central

    Lee, Heon-Jin; Caldwell, Heather K.; Macbeth, Abbe H.; Tolu, Selen G.; Young, W. Scott

    2008-01-01

    Oxytocin plays important roles in reproductive physiology and various behaviors, including maternal behavior and social memory. Its receptor (Oxtr) is present in peripheral tissues and brain, so a conditional knockout (KO, −/−) would be useful to allow elimination of the receptor in specific sites at defined times. We created a line of mice in which loxP sites flank Oxtr coding sequence (floxed) enable Cre recombinase-mediated inactivation of the receptor. We expressed Cre recombinase in these mice either in all tissues (Oxtr−/−) or the forebrain (OxtrFB/FB) using the Ca2+/calmodulin-dependent protein kinase IIα promoter. The latter KO has reduced Oxtr binding beginning 21–28 d postnatally, leading to prominent reductions in the lateral septum, hippocampus, and ventral pallidum. The medial amygdala is spared, and there is significant retention of binding within the olfactory bulb and nucleus and neocortex. We did not observe any deficits in the general health, sensorimotor functions, anxiety-like behaviors, or sucrose intake in either Oxtr−/− or OxtrFB/FB mice. Females of both KO types deliver pups, but only the OxtrFB/FB mice are able to eject milk. Oxtr−/− males show impaired social memory for familiar females, whereas the OxtrFB/FB males appear to recognize their species but not individuals. Our results confirm the importance of oxytocin in social recognition and demonstrate that spatial and temporal inactivation of the Oxtr will enable finer understanding of the physiological, behavioral, and developmental roles of the receptor. PMID:18356275

  11. Type 3 Muscarinic Receptors Contribute to Clearance of Citrobacter rodentium

    PubMed Central

    McLean, Leon P.; Smith, Allen; Cheung, Lumei; Sun, Rex; Grinchuk, Viktoriya; Vanuytsel, Tim; Desai, Neemesh; Urban, Joseph F.; Zhao, Aiping; Raufman, Jean-Pierre; Shea-Donohue, Terez

    2016-01-01

    Background The role of muscarinic receptors in mucosal homeostasis, response to enteric pathogens, and modulation of immune cell function is undefined. Methods The contribution of type 3 muscarinic receptors (M3R) to mucosal homeostasis within the colon and host defense against Citrobacter rodentium was determined in uninfected and C. rodentium-infected WT and M3R-deficient (Chrm3−/−) mice. In addition, WT and Chrm3−/− bone marrow-derived macrophages (BMDM) were studied to determine the ability of M3R to modulate macrophage phenotype and function. Results In Chrm3−/− mice clearance of C. rodentium was delayed despite an amplified TH1/TH17 response. Delayed clearance of C. rodentium from Chrm3−/− mice was associated with prolonged adherence of bacteria to colonic mucosa, decreased goblet cell number, and decreased mucin 2 gene expression. Treatment of BMDM with bethanechol, a muscarinic-selective agonist, induced a classically activated macrophage phenotype, which was dependent on M3R expression. Chrm3−/− BMDM retained their ability to attain a classically activated macrophage phenotype when treated with the TH1 cytokine IFN-γ. Conclusions In Chrm3−/− mice mucin production is attenuated and is associated with prolonged adherence of C. rodentium to colonic mucosa. The immune response, as characterized by production of TH1/TH17 cytokines, in C. rodentium-infected Chrm3−/− mice is intact. In addition, M3R activity promotes the development of classically activated macrophages. Our data establish a role for M3R in host defense against C. rodentium through effects on goblet cell mucus production and in the modulation of macrophage phenotype and function. PMID:25985244

  12. VARIATION IN THE OXYTOCIN RECEPTOR GENE IS ASSOCIATED WITH INCREASED RISK FOR ANXIETY, STRESS AND DEPRESSION IN INDIVIDUALS WITH A HISTORY OF EXPOSURE TO EARLY LIFE STRESS

    PubMed Central

    Myers, Amanda J.; Williams, Leanne; Gatt, Justine M.; McAuley-Clark, Erica Z.; Dobson-Stone, Carol; Schofield, Peter R.; Nemeroff, Charles B.

    2014-01-01

    Background Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression. Methods In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples. Results A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associated with differences in DASS scores with one SNP (rs139832701) showing significant association or a trend towards association for all three measures. Several OXTR SNPs were correlated with alterations in OXTR RNA expression and rs3831817 replicated across both sets of tissues. Conclusions These results support the hypothesis that the oxytocin system plays a role in the pathophysiology of mood and anxiety disorders. PMID:25262417

  13. Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization.

    PubMed

    Grotegut, Chad A; Mao, Lan; Pierce, Stephanie L; Swamy, Geeta K; Heine, R Phillips; Murtha, Amy P

    2016-04-01

    Oxytocin is a potent uterotonic agent and is used clinically for induction and augmentation of labor, as well as for prevention and treatment of postpartum hemorrhage. Oxytocin increases uterine contractility by activating the oxytocin receptor (OXTR), a member of the G protein-coupled receptor family, which is prone to molecular desensitization. After oxytocin binding, the OXTR is phosphorylated by a member of the G protein-coupled receptor kinase (GRK) family, which allows for recruitment of β-arrestin, receptor internalization, and desensitization. According to previous in vitro analyses, desensitization of calcium signaling by the OXTR is mediated by GRK6. The objective of this study was to determine the role of GRK6 in mediating uterine contractility. Here, we demonstrate that uterine GRK6 levels increase in pregnancy and using a telemetry device to measure changes in uterine contractility in live mice during labor, show that mice lacking GRK6 produce a phenotype of enhanced uterine contractility during both spontaneous and oxytocin-induced labor compared with wild-type or GRK5 knockout mice. In addition, the observed enhanced contractility was associated with high rates of term stillbirth. Lastly, using a heterologous in vitro model, we show that β-arrestin recruitment to the OXTR, which is necessary for homologous OXTR desensitization, is dependent on GRK6. Our findings suggest that GRK6-mediated OXTR desensitization in labor is necessary for normal uterine contractile patterns and optimal fetal outcome. PMID:26886170

  14. Oxytocin receptor DNA methylation in postpartum depression.

    PubMed

    Kimmel, Mary; Clive, Makena; Gispen, Fiona; Guintivano, Jerry; Brown, Tori; Cox, Olivia; Beckmann, Matthias W; Kornhuber, Johannes; Fasching, Peter A; Osborne, Lauren M; Binder, Elisabeth; Payne, Jennifer L; Kaminsky, Zachary

    2016-07-01

    The oxytocin receptor (OXTR) is a key regulator of stress and anxiety and may be regulated by both psychosocial risk factors and gonadal hormones, making it an attractive candidate for study in postpartum depression (PPD). The objective of this study was to investigate both serum hormone and PPD specific DNA methylation variation in the OXTR. Illumina HM450 microarray data generated in a prospective PPD cohort identified significant associations (P=0.014) with PPD in an intronic region in the OXTR located 4bp proximal to an estrogen receptor (ER) binding region. Pyrosequencing confirmed moderate evidence for an interaction of CpGs in the region with childhood abuse status to mediate PPD. These CpGs located on chr3 at positions 8810078 and 8810069 exhibited significant associations with postpartum depression scores from an independent cohort of 240 women with no prior psychiatric history. Hormone analysis suggested a PPD specific negative correlation of DNA methylation in the region with serum estradiol levels. Estradiol levels and OXTR DNA methylation exhibited a significant interaction to associate with the ratio of allopregnanolone to progesterone. Cumulatively, the data corroborate our previous hypotheses of a PPD specific increased sensitivity of epigenetic reprogramming at estrogen target genes and suggests that OXTR epigenetic variation may be an important mediator of mood relevant neuroactive steroid production. PMID:27108164

  15. Oxytocin receptor gene methylation: converging multilevel evidence for a role in social anxiety.

    PubMed

    Ziegler, Christiane; Dannlowski, Udo; Bräuer, David; Stevens, Stephan; Laeger, Inga; Wittmann, Hannah; Kugel, Harald; Dobel, Christian; Hurlemann, René; Reif, Andreas; Lesch, Klaus-Peter; Heindel, Walter; Kirschbaum, Clemens; Arolt, Volker; Gerlach, Alexander L; Hoyer, Jürgen; Deckert, Jürgen; Zwanzger, Peter; Domschke, Katharina

    2015-05-01

    Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study-for the first time applying a multilevel epigenetic approach-investigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (p<0.001, Cohen's d=0.535), (2) increased SPS and SIAS scores (p<0.001), (3) increased cortisol response to the TSST (p=0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: p(corr)<0.001; left: p(corr)=0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system. PMID:25563749

  16. Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

    PubMed Central

    Ziegler, Christiane; Dannlowski, Udo; Bräuer, David; Stevens, Stephan; Laeger, Inga; Wittmann, Hannah; Kugel, Harald; Dobel, Christian; Hurlemann, René; Reif, Andreas; Lesch, Klaus-Peter; Heindel, Walter; Kirschbaum, Clemens; Arolt, Volker; Gerlach, Alexander L; Hoyer, Jürgen; Deckert, Jürgen; Zwanzger, Peter; Domschke, Katharina

    2015-01-01

    Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study—for the first time applying a multilevel epigenetic approach—investigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (p<0.001, Cohen's d=0.535), (2) increased SPS and SIAS scores (p<0.001), (3) increased cortisol response to the TSST (p=0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: pcorr<0.001; left: pcorr=0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system. PMID:25563749

  17. Association between Oxytocin Receptor Gene Polymorphisms and Self-Rated ‘Empathic Concern’ in Schizophrenia

    PubMed Central

    Montag, Christiane; Brockmann, Eva-Maria; Lehmann, Anja; Müller, Daniel J.; Rujescu, Dan; Gallinat, Jürgen

    2012-01-01

    The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive (‘perspective taking’), affective (‘empathic concern’) and self-related (‘personal distress’) dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282] = 10.464; p<0.01) and interaction effect (genotype by diagnosis: F [1,282] = 4.329; p<0.05) of OXTR SNP rs2254298(A>GG) with ‘empathic concern’. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with ‘empathic concern’. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI ‘perspective taking’ or ‘personal distress’ ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication. PMID:23284802

  18. Association between oxytocin receptor gene polymorphisms and self-rated 'empathic concern' in schizophrenia.

    PubMed

    Montag, Christiane; Brockmann, Eva-Maria; Lehmann, Anja; Müller, Daniel J; Rujescu, Dan; Gallinat, Jürgen

    2012-01-01

    The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive ('perspective taking'), affective ('empathic concern') and self-related ('personal distress') dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282] = 10.464; p<0.01) and interaction effect (genotype by diagnosis: F [1,282] = 4.329; p<0.05) of OXTR SNP rs2254298(A>GG) with 'empathic concern'. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with 'empathic concern'. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI 'perspective taking' or 'personal distress' ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication. PMID:23284802

  19. Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats.

    PubMed

    Beery, Annaliese K; McEwen, Lisa M; MacIsaac, Julia L; Francis, Darlene D; Kobor, Michael S

    2016-01-01

    This article is part of a Special Issue "Parental Care". Since the first report of maternal care effects on DNA methylation in rats, epigenetic modifications of the genome in response to life experience have become the subject of intense focus across many disciplines. Oxytocin receptor expression varies in response to early experience, and both oxytocin signaling and methylation status of the oxytocin receptor gene (Oxtr) in blood have been related to disordered social behavior. It is unknown whether Oxtr DNA methylation varies in response to early life experience, and whether currently employed peripheral measures of Oxtr methylation reflect variation in the brain. We examined the effects of early life rearing experience via natural variation in maternal licking and grooming during the first week of life on behavior, physiology, gene expression, and epigenetic regulation of Oxtr across blood and brain tissues (mononucleocytes, hippocampus, striatum, and hypothalamus). Rats reared by "high" licking-grooming (HL) and "low" licking-grooming (LL) rat dams exhibited differences across study outcomes: LL offspring were more active in behavioral arenas, exhibited lower body mass in adulthood, and showed reduced corticosterone responsivity to a stressor. Oxtr DNA methylation was significantly lower at multiple CpGs in the blood of LL versus HL males, but no differences were found in the brain. Across groups, Oxtr transcript levels in the hypothalamus were associated with reduced corticosterone secretion in response to stress, congruent with the role of oxytocin signaling in this region. Methylation of specific CpGs at a high or low level was consistent across tissues, especially within the brain. However, individual variation in DNA methylation relative to these global patterns was not consistent across tissues. These results suggest that blood Oxtr DNA methylation may reflect early experience of maternal care, and that Oxtr methylation across tissues is highly concordant

  20. Neuroanatomical distribution of oxytocin and vasopressin 1a receptors in the socially monogamous coppery titi monkey (Callicebus cupreus)

    PubMed Central

    Freeman, Sara M.; Walum, Hasse; Inoue, Kiyoshi; Smith, Aaron L.; Goodman, Mark M.; Bales, Karen L.; Young, Larry J.

    2014-01-01

    The coppery titi monkey (Callicebus cupreus) is a socially monogamous New World primate that has been studied in the field and the laboratory to investigate the behavioral neuroendocrinology of primate pair bonding and parental care. Arginine vasopressin has been shown to influence male titi monkey pair-bonding behavior, and studies are currently underway to examine the effects of oxytocin on titi monkey behavior and physiology. Here, we use receptor autoradiography to identify the distribution of arginine vasopressin 1a (AVPR1a) and oxytocin receptors (OXTR) in hemispheres of titi monkey brain (n=5). AVPR1a are diffuse and widespread throughout the brain, but the OXTR distribution is much more limited, with the densest binding being in the hippocampal formation (dentate gyrus, CA1 field) and the presubiculum (layers I and III). Moderate OXTR binding was detected in the nucleus basalis of Meynert, pulvinar, superior colliculus, layer 4C of primary visual cortex, periaqueductal gray, pontine gray, nucleus prepositus, and spinal trigeminal nucleus. OXTR mRNA overlapped with OXTR radioligand binding, confirming that the radioligand was detecting OXTR protein. AVPR1a binding is present throughout the cortex, especially in cingulate, insular, and occipital cortices, as well as in the caudate, putamen, nucleus accumbens, central amygdala, endopiriform nucleus, hippocampus (CA4 field), globus pallidus, lateral geniculate nucleus, infundibulum, habenula, periaqueductal gray, substantia nigra, olivary nucleus, hypoglossal nucleus, and cerebellum. Furthermore, we show that, in titi monkey brain, the OXTR antagonist ALS-II-69 is highly selective for OXTR and that the AVPR1a antagonist SR49059 is highly selective for AVPR1a. Based on these results and the fact that both ALS-II-69 and SR49059 are non-peptide, small-molecule antagonists that should be capable of crossing the blood brain barrier, these two compounds emerge as excellent candidates for the pharmacological

  1. Antisocial behavior and polymorphisms in the oxytocin receptor gene: findings in two independent samples.

    PubMed

    Hovey, D; Lindstedt, M; Zettergren, A; Jonsson, L; Johansson, A; Melke, J; Kerekes, N; Anckarsäter, H; Lichtenstein, P; Lundström, S; Westberg, L

    2016-07-01

    The quantitative genetic contribution to antisocial behavior is well established, but few, if any, genetic variants are established as risk factors. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may modulate interpersonal aggression. We here investigated whether single-nucleotide polymorphisms (SNPs) in the OXT receptor gene (OXTR) are associated with the expression of antisocial behavior. A discovery sample, including both sexes, was drawn from the Child and Adolescent Twin Study in Sweden (CATSS; n=2372), and a sample from the Twin Study of Child and Adolescent Development (TCHAD; n=1232) was used for replication. Eight SNPs in OXTR, selected on previous associations with social and antisocial behavior, were genotyped in the participants of CATSS. Significant polymorphisms were subsequently genotyped in TCHAD for replication. Participants completed self-assessment questionnaires-Life History of Aggression (LHA; available only in CATSS), and Self-Reported Delinquency (SRD; available in both samples)-designed to capture antisocial behavior as continuous traits. In the discovery sample, the rs7632287 AA genotype was associated with higher frequency of antisocial behavior in boys, and this was then replicated in the second sample. In particular, overt aggression (directly targeting another individual) was strongly associated with this genotype in boys (P=6.2 × 10(-7) in the discovery sample). Meta-analysis of the results for antisocial behavior from both samples yielded P=2.5 × 10(-5). Furthermore, an association between rs4564970 and LHA (P=0.00013) survived correction in the discovery sample, but there was no association with the SRD in the replication sample. We conclude that the rs7632287 and rs4564970 polymorphisms in OXTR may independently influence antisocial behavior in adolescent boys. Further replication of our results will be crucial to understanding how aberrant social behavior arises, and would support the OXT receptor as one

  2. Endoplasmic reticulum stress contributes to acetylcholine receptor degradation by promoting endocytosis in skeletal muscle cells.

    PubMed

    Du, Ailian; Huang, Shiqian; Zhao, Xiaonan; Zhang, Yun; Zhu, Lixun; Ding, Ji; Xu, Congfeng

    2016-01-15

    After binding by acetylcholine released from a motor neuron, a nicotinic acetylcholine receptor at the neuromuscular junction produces a localized end-plate potential, which leads to muscle contraction. Improper turnover and renewal of acetylcholine receptors contributes to the pathogenesis of myasthenia gravis. In the present study, we demonstrate that endoplasmic reticulum (ER) stress contributes to acetylcholine receptor degradation in C2C12 myocytes. We further show that ER stress promotes acetylcholine receptor endocytosis and lysosomal degradation, which was dampened by blocking endocytosis or treating with lysosome inhibitor. Knockdown of ER stress proteins inhibited acetylcholine receptor endocytosis and degradation, while rescue assay restored its endocytosis and degradation, confirming the effects of ER stress on promoting endocytosis-mediated degradation of junction acetylcholine receptors. Thus, our studies identify ER stress as a factor promoting acetylcholine receptor degradation through accelerating endocytosis in muscle cells. Blocking ER stress and/or endocytosis might provide a novel therapeutic approach for myasthenia gravis. PMID:26711579

  3. Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

    PubMed

    Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

    2016-01-01

    Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD. PMID:27552585

  4. N-Methyl-D-Aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity

    EPA Science Inventory

    N-Methyl-D-aspartate Receptor Activation May Contribute to Glufosinate Neurotoxicity Glufosinate (GLF) at high levels in mammals causes convulsions through a mechanism that is not completely understood. The structural similarity of GLF to glutamate (GLU) implicates the glutamate...

  5. Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain.

    PubMed

    Puglia, Meghan H; Lillard, Travis S; Morris, James P; Connelly, Jessica J

    2015-03-17

    In humans, the neuropeptide oxytocin plays a critical role in social and emotional behavior. The actions of this molecule are dependent on a protein that acts as its receptor, which is encoded by the oxytocin receptor gene (OXTR). DNA methylation of OXTR, an epigenetic modification, directly influences gene transcription and is variable in humans. However, the impact of this variability on specific social behaviors is unknown. We hypothesized that variability in OXTR methylation impacts social perceptual processes often linked with oxytocin, such as perception of facial emotions. Using an imaging epigenetic approach, we established a relationship between OXTR methylation and neural activity in response to emotional face processing. Specifically, high levels of OXTR methylation were associated with greater amounts of activity in regions associated with face and emotion processing including amygdala, fusiform, and insula. Importantly, we found that these higher levels of OXTR methylation were also associated with decreased functional coupling of amygdala with regions involved in affect appraisal and emotion regulation. These data indicate that the human endogenous oxytocin system is involved in attenuation of the fear response, corroborating research implicating intranasal oxytocin in the same processes. Our findings highlight the importance of including epigenetic mechanisms in the description of the endogenous oxytocin system and further support a central role for oxytocin in social cognition. This approach linking epigenetic variability with neural endophenotypes may broadly explain individual differences in phenotype including susceptibility or resilience to disease. PMID:25675509

  6. Interaction between oxytocin receptor polymorphism and interdependent culture values on human empathy

    PubMed Central

    Luo, Siyang; Ma, Yina; Liu, Yi; Li, Bingfeng; Wang, Chenbo; Shi, Zhenhao; Li, Xiaoyang; Zhang, Wenxia; Rao, Yi

    2015-01-01

    Recent evidence suggests that the association between oxytocin receptor polymorphism (OXTR rs53576) and emotion-related behavioral/psychological tendencies differs between individuals from East Asian and Western cultures. What remains unresolved is which specific dimension of cultural orientations interacts with OXTR rs53576 to shape these tendencies and whether such gene × culture interactions occurs at both behavioral and neural level. This study investigated whether and how OXTR rs53576 interacts with interdependence—a key dimension of cultural orientations that distinguish between East Asian and Western cultures—to affect human empathy that underlies altruistic motivation and prosocial behavior. Experiment 1 measured interdependence, empathy trait and OXTR rs53576 genotypes of 1536 Chinese participants. Hierarchical regression analyses revealed a stronger association between interdependence and empathy trait in G allele carriers compared with A/A homozygotes of OXTR rs53576. Experiment 2 measured neural responses to others’ suffering by scanning A/A and G/G homozygous of OXTR rs53576 using functional magnetic resonance imaging. Hierarchical regression analyses revealed stronger associations between interdependence and empathic neural responses in the insula, amygdala and superior temporal gyrus in G/G compared with A/A carriers. Our results provide the first evidence for gene × culture interactions on empathy at both behavioral tendency and underlying brain activity. PMID:25680993

  7. Carbetocin is a Functional Selective Gq Agonist That Does Not Promote Oxytocin Receptor Recycling After Inducing β-Arrestin-Independent Internalisation.

    PubMed

    Passoni, I; Leonzino, M; Gigliucci, V; Chini, B; Busnelli, M

    2016-04-01

    Carbetocin, a long-acting oxytocin analogue, has been reported to elicit interesting and peculiar behavioural effects. The present study investigated the molecular pharmacology of carbetocin, aiming to better understand the molecular basis of its action in the brain. Using bioluminescence resonance energy transfer biosensors, we characterised the effects of carbetocin on the three human oxytocin/vasopressin receptors expressed in the nervous system: the oxytocin receptor (OXTR) and the vasopressin V1a (V1aR) and V1b (V1bR) receptors. Our results indicate that (i) carbetocin activates the OXTR but not the V1aR and V1bR at which it may act as an antagonist; (ii) carbetocin selectively activates only the OXTR/Gq pathway displaying a strong functional selectivity; (iii) carbetocin is a partial agonist at the OXTR/Gq coupling; (iv) carbetocin promotes OXTR internalisation via a previously unreported β-arrestin-independent pathway; and (v) carbetocin does not induce OXTR recycling to the plasma membrane. Altogether, these molecular pharmacology features identify carbetocin as a substantially different analogue compared to the endogenous oxytocin and, consequently, carbetocin is not expected to mimic oxytocin in the brain. Whether these unique features of carbetocin could be exploited therapeutically remains to be established. PMID:26751410

  8. Leaky ryanodine receptors contribute to diaphragmatic weakness during mechanical ventilation.

    PubMed

    Matecki, Stefan; Dridi, Haikel; Jung, Boris; Saint, Nathalie; Reiken, Steven R; Scheuermann, Valérie; Mrozek, Ségolène; Santulli, Gaetano; Umanskaya, Alisa; Petrof, Basil J; Jaber, Samir; Marks, Andrew R; Lacampagne, Alain

    2016-08-01

    Ventilator-induced diaphragmatic dysfunction (VIDD) refers to the diaphragm muscle weakness that occurs following prolonged controlled mechanical ventilation (MV). The presence of VIDD impedes recovery from respiratory failure. However, the pathophysiological mechanisms accounting for VIDD are still not fully understood. Here, we show in human subjects and a mouse model of VIDD that MV is associated with rapid remodeling of the sarcoplasmic reticulum (SR) Ca(2+) release channel/ryanodine receptor (RyR1) in the diaphragm. The RyR1 macromolecular complex was oxidized, S-nitrosylated, Ser-2844 phosphorylated, and depleted of the stabilizing subunit calstabin1, following MV. These posttranslational modifications of RyR1 were mediated by both oxidative stress mediated by MV and stimulation of adrenergic signaling resulting from the anesthesia. We demonstrate in the murine model that such abnormal resting SR Ca(2+) leak resulted in reduced contractile function and muscle fiber atrophy for longer duration of MV. Treatment with β-adrenergic antagonists or with S107, a small molecule drug that stabilizes the RyR1-calstabin1 interaction, prevented VIDD. Diaphragmatic dysfunction is common in MV patients and is a major cause of failure to wean patients from ventilator support. This study provides the first evidence to our knowledge of RyR1 alterations as a proximal mechanism underlying VIDD (i.e., loss of function, muscle atrophy) and identifies RyR1 as a potential target for therapeutic intervention. PMID:27457930

  9. Ryanodine receptors contribute to the induction of ischemic tolerance.

    PubMed

    Nakamura-Maruyama, Emi; Miyamoto, Osamu; Okabe, Naohiko; Himi, Naoyuki; Feng, Lu; Narita, Kazuhiko; Keep, Richard F; Yamamoto, Tohru; Nakamura, Takehiro

    2016-04-01

    Ischemic tolerance (IT) is induced by a variety of insults to the brain (e.g., nonfatal ischemia, heat and hypoxia) and it provides a strong neuroprotective effect. Although the mechanisms are still not fully elucidated, Ca(2+) is regarded as a key mediator of IT. Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca(2+) from intracellular stores. In brain, neuronal RyRs are thought to play a role in various neuropathological conditions, including ischemia. The purpose of the present study was to investigate the involvement of RyRs in IT. Pretreatment with a RyR antagonist, dantrolene (25mg/kg, i.p), blocked IT in a gerbil global ischemia model, while a RyR agonist, caffeine (100mg/kg, i.p), stimulated the production of IT. In vitro, using rat hippocampal cells, short-term oxygen/glucose deprivation induced preconditioning and RyR antagonists, dantrolene (50 and 100μM) and ryanodine (100 and 200μM) prevented it. RyR protein and mRNA levels were transiently decreased after induction of IT. These results suggest that RyRs are involved in the induction of ischemic tolerance. PMID:26930163

  10. Oxytocin receptor gene sequences in owl monkeys and other primates show remarkable interspecific regulatory and protein coding variation.

    PubMed

    Babb, Paul L; Fernandez-Duque, Eduardo; Schurr, Theodore G

    2015-10-01

    The oxytocin (OT) hormone pathway is involved in numerous physiological processes, and one of its receptor genes (OXTR) has been implicated in pair bonding behavior in mammalian lineages. This observation is important for understanding social monogamy in primates, which occurs in only a small subset of taxa, including Azara's owl monkey (Aotus azarae). To examine the potential relationship between social monogamy and OXTR variation, we sequenced its 5' regulatory (4936bp) and coding (1167bp) regions in 25 owl monkeys from the Argentinean Gran Chaco, and examined OXTR sequences from 1092 humans from the 1000 Genomes Project. We also assessed interspecific variation of OXTR in 25 primate and rodent species that represent a set of phylogenetically and behaviorally disparate taxa. Our analysis revealed substantial variation in the putative 5' regulatory region of OXTR, with marked structural differences across primate taxa, particularly for humans and chimpanzees, which exhibited unique patterns of large motifs of dinucleotide A+T repeats upstream of the OXTR 5' UTR. In addition, we observed a large number of amino acid substitutions in the OXTR CDS region among New World primate taxa that distinguish them from Old World primates. Furthermore, primate taxa traditionally defined as socially monogamous (e.g., gibbons, owl monkeys, titi monkeys, and saki monkeys) all exhibited different amino acid motifs for their respective OXTR protein coding sequences. These findings support the notion that monogamy has evolved independently in Old World and New World primates, and that it has done so through different molecular mechanisms, not exclusively through the oxytocin pathway. PMID:26025428

  11. Genetic variation in the oxytocin receptor gene is associated with a social phenotype in autism spectrum disorders.

    PubMed

    Harrison, Ashley J; Gamsiz, Ece D; Berkowitz, Isaac C; Nagpal, Shailender; Jerskey, Beth A

    2015-12-01

    Oxytocin regulates social behavior in animal models. Research supports an association between genetic variation in the oxytocin receptor gene (OXTR) and autism spectrum disorders (ASD). In this study, we examine the association between the OXTR gene and a specific social phenotype within ASD. This genotype-phenotype investigation may provide insight into how OXTR conveys risk for social impairment. The current study investigated 10 SNPS in the OXTR gene that have been previously shown to be associated with ASD. We examine the association of these SNPs with both a social phenotype and a repetitive behavior phenotype comprised of behaviors commonly impaired in ASD in the Simons simplex collection (SSC). Using a large sample to examine the association between OXTR and ASD (n = range: 485-1002), we find evidence to support a relation between two OXTR SNPs and the examined social phenotype among children diagnosed with ASD. Greater impairment on the social responsiveness scale standardized total score and on several subdomains was observed among individuals with one or more copies of the minor frequency allele in both rs7632287 and rs237884. Linkage disequilibrium (LD) mapping suggests that these two SNPs are in LD within and overlapping the 3' untranslated region (3'-UTR) of the OXTR gene. These two SNPs were also associated with greater impairment on the repetitive behavior scale. Results of this study indicate that social impairment and repetitive behaviors in ASD are associated with genomic variation in the 3'UTR of the OXTR gene. These variants may be linked to an allele that alters stability of the mRNA message although further work is necessary to test this hypothesis. PMID:26365303

  12. Heterogeneity and probabilistic binding contributions to receptor-mediated cell detachment kinetics.

    PubMed Central

    Saterbak, A; Kuo, S C; Lauffenburger, D A

    1993-01-01

    Biospecific cell adhesion is mediated by receptor-ligand bonds. Early theoretical work presented a deterministic analysis of receptor-mediated cell attachment and detachment for a homogeneous cell population. However, initial comparison of a deterministic framework to experimental detachment profiles of model "cells" (antibody-coated latex beads) did not show qualitative or quantitative agreement (Cozens-Roberts, C., D.A. Lauffenburger, and J.A. Quinn. 1990. Biophys. J. 58:857-872). Hence, we determine the contributions of population heterogeneity and probabilistic binding to the detachment behavior of this experimental system which was designed to minimize experimental and theoretical complications. This work also corrects an error in the numerical solution of the probabilistic model of receptor-mediated cell attachment and detachment developed previously (Cozens-Roberts, C., D.A. Lauffenburger, and J.A. Quinn. 1990. Biophys J. 58:841-856). Measurement of the population distribution of the number of receptors per bead has enabled us to explicitly consider the effect of receptor number heterogeneity within the cell-surface contact area. A deterministic framework that incorporates receptor number heterogeneity qualitatively and quantitatively accounts in large part for the model cell detachment data. Using measured and estimated parameter values for the model cell system, we estimate that about 90% of the observed kinetic detachment behavior originates from heterogeneity effects, while about 10% is due to probabilistic binding effects. In general, these relative contributions may differ for other systems. PMID:8396454

  13. Contributions of sex, testosterone, and androgen receptor CAG repeat number to virtual Morris water maze performance.

    PubMed

    Nowak, Nicole T; Diamond, Michael P; Land, Susan J; Moffat, Scott D

    2014-03-01

    The possibility that androgens contribute to the male advantage typically found on measures of spatial cognition has been investigated using a variety of approaches. To date, evidence to support the notion that androgens affect spatial cognition in healthy young adults is somewhat equivocal. The present study sought to clarify the association between testosterone (T) and spatial performance by extending measurements of androgenicity to include both measures of circulating T as well as an androgen receptor-specific genetic marker. The aims of this study were to assess the contributions of sex, T, and androgen receptor CAG repeat number (CAGr) on virtual Morris water task (vMWT) performance in a group of healthy young men and women. The hypothesis that men would outperform women on vMWT outcomes was supported. Results indicate that CAGr may interact with T to impact navigation performance and suggest that consideration of androgen receptor sensitivity is an important consideration in evaluating hormone-behavior relationships. PMID:24495604

  14. Tachykinins and Their Receptors: Contributions to Physiological Control and the Mechanisms of Disease

    PubMed Central

    Steinhoff, Martin S.; von Mentzer, Bengt; Geppetti, Pierangelo; Pothoulakis, Charalabos; Bunnett, Nigel W.

    2014-01-01

    The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists. PMID:24382888

  15. Serotonin 2A receptors contribute to the regulation of risk-averse decisions

    PubMed Central

    Macoveanu, Julian; Rowe, James B; Hornboll, Bettina; Elliott, Rebecca; Paulson, Olaf B; Knudsen, Gitte M; Siebner, Hartwig R

    2013-01-01

    Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5-HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were balanced in terms of expected utility and potential loss. Acute blockade of the 5-HT2A receptors with ketanserin made participants more risk-averse. Ketanserin selectively reduced the neural response of the frontopolar cortex to negative outcomes that were caused by low-risk choices and were associated with large missed rewards. In the context of normal 5-HT2A receptor function, ventral striatum displayed a stronger response to low-risk negative outcomes in risk-taking as opposed to risk-averse individuals. This (negative) correlation between the striatal response to low-risk negative outcomes and risk-averse choice behavior was abolished by 5-HT2A receptor blockade. The results provide the first evidence for a critical role of 5-HT2A receptor function in regulating risk-averse behavior. We suggest that the 5-HT2A receptor system facilitates risk-taking behavior by modulating the outcome evaluation of “missed” reward. These results have implications for understanding the neural basis of abnormal risk-taking behavior, for instance in pathological gamblers. PMID:23810974

  16. Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure.

    PubMed

    Arnold, Amy C; Okamoto, Luis E; Gamboa, Alfredo; Black, Bonnie K; Raj, Satish R; Elijovich, Fernando; Robertson, David; Shibao, Cyndya A; Biaggioni, Italo

    2016-02-01

    Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson's disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P=0.492; nocturnal weight loss: -1.19±0.15 kg placebo versus -1.18±0.15 kg eplerenone, P=0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients. PMID:26644241

  17. Contribution of NMDA receptors to dorsolateral prefrontal cortical networks in primates.

    PubMed

    Wang, Min; Arnsten, Amy F T

    2015-04-01

    Cognitive disorders such as schizophrenia and Alzheimer's disease are associated with dysfunction of the highly evolved dorsolateral prefrontal cortex (dlPFC), and with changes in glutamatergic N-methyl-D-aspartate receptors (NMDARs). Recent research on the primate dlPFC discovered that the pyramidal cell circuits that generate the persistent firing underlying spatial working memory communicate through synapses on spines containing NMDARs with NR2B subunits (GluN2B) in the post-synaptic density. This contrasts with synapses in the hippocampus and primary visual cortex, where GluN2B receptors are both synaptic and extrasynaptic. Blockade of GluN2B in the dlPFC markedly reduces the persistent firing of the Delay cells needed for neuronal representations of visual space. Cholinergic stimulation of nicotinic α7 receptors within the glutamate synapse is necessary for NMDAR actions. In contrast, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors have only subtle effects on the persistent firing of Delay cells, but contribute substantially to the firing of Cue and Response cells. Systemic administration of the NMDAR antagonist ketamine reduces the persistent firing of Delay cells, but increases the firing of some Response cells. The reduction in persistent firing produced by ketamine may explain why this drug can mimic or worsen the cognitive symptoms of schizophrenia. Similar actions in the medial PFC circuits representing the emotional aspects of pain may contribute to the rapid analgesic and anti-depressant actions of ketamine. PMID:25754145

  18. On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors.

    PubMed

    Fedder, Karlie N; Sabo, Shasta L

    2015-01-01

    Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs) contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases. PMID:26694480

  19. On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors

    PubMed Central

    Fedder, Karlie N.; Sabo, Shasta L.

    2015-01-01

    Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs) contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases. PMID:26694480

  20. Activation by SLAM Family Receptors Contributes to NK Cell Mediated “Missing-Self” Recognition

    PubMed Central

    Alari-Pahissa, Elisenda; Grandclément, Camille; Jeevan-Raj, Beena; Leclercq, Georges; Veillette, André; Held, Werner

    2016-01-01

    Natural Killer (NK) cells attack normal hematopoietic cells that do not express inhibitory MHC class I (MHC-I) molecules, but the ligands that activate NK cells remain incompletely defined. Here we show that the expression of the Signaling Lymphocyte Activation Molecule (SLAM) family members CD48 and Ly9 (CD229) by MHC-I-deficient tumor cells significantly contributes to NK cell activation. When NK cells develop in the presence of T cells or B cells that lack inhibitory MHC-I but express activating CD48 and Ly9 ligands, the NK cells’ ability to respond to MHC-I-deficient tumor cells is severely compromised. In this situation, NK cells express normal levels of the corresponding activation receptors 2B4 (CD244) and Ly9 but these receptors are non-functional. This provides a partial explanation for the tolerance of NK cells to MHC-I-deficient cells in vivo. Activating signaling via 2B4 is restored when MHC-I-deficient T cells are removed, indicating that interactions with MHC-I-deficient T cells dominantly, but not permanently, impair the function of the 2B4 NK cell activation receptor. These data identify an important role of SLAM family receptors for NK cell mediated “missing-self” reactivity and suggest that NK cell tolerance in MHC-I mosaic mice is in part explained by an acquired dysfunction of SLAM family receptors. PMID:27054584

  1. Contribution of CCK1 receptors to cardiovascular and respiratory effects of cholecystokinin in anesthetized rats.

    PubMed

    Kaczyńska, Katarzyna; Szereda-Przestaszewska, Małgorzata

    2015-12-01

    The study investigated the share of vagal input at infra- and supra-nodosal level and the contribution of CCK1 and CCK2 receptors to the cardiorespiratory responses produced by an intravenous injection of sulfated cholecystokinin octapeptide (CCK-8) in anesthetized rats. This compound administered intravenously at a dose of 50μg/kg induced short-lived decline in tidal volume and respiratory rate resulting in depression of minute ventilation. Midcervical vagotomy had no effect on CCK-8-evoked ventilatory changes, whereas supranodosal denervation abolished slowing down of breathing. Cardiovascular response to CCK challenge was characterized by a transient decrease followed by an augmentation in the mean blood pressure (MAP) in the intact animals. Vagotomy performed at both levels abrogated the declining phase of MAP. Blood pressure changes were associated with decreased heart rate present in all neural states. All cardiovascular and respiratory effects were antagonized by pre-treatment with devazepide-CCK1 receptors' antagonist, whereas CI988-antagonist of CCK2 receptors was ineffective. In conclusion, our results indicate that CCK-8 modulates slowing down of respiratory rhythm via CCK1 receptors located in the nodose ganglia (NG) and depresses tidal volume via central CCK1 dependent mechanism. CCK-8-evoked decline in blood pressure may be due to activation of vagal afferents, whereas pressor responses seem to be mediated by an activation of CCK1 receptors in the central nervous system. Bradycardia was probably induced by the direct action of CCK-8 on the heart pacemaker cells. PMID:26342277

  2. Lack of dopamine D4 receptor affinity contributes to the procognitive effect of lurasidone.

    PubMed

    Murai, Takeshi; Nakako, Tomokazu; Ikeda, Kazuhito; Ikejiri, Masaru; Ishiyama, Takeo; Taiji, Mutsuo

    2014-03-15

    We previously demonstrated among several antipsychotics exhibiting potent dopamine D2 receptor antagonism that only lurasidone, (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1] heptanedicarboximide hydrochloride, improved performance in the object retrieval detour (ORD) task by marmosets. The mechanisms by which only lurasidone causes enhancements in cognitive function have not yet been established; however, most antipsychotics, except for lurasidone, have been shown to exhibit potent antagonistic activity against the dopamine D4 receptor. The objectives of this study were to evaluate the role of the dopamine D4 receptor on executive function with the selective agonist, Ro10-5824 and antagonist, L-745,870, and elucidate a possible mechanism for the procognitive effect of lurasidone. The effects of these drugs were evaluated in naïve marmosets using the ORD task. Changes in the success rate during the difficult trial in the task were used to assess the cognitive effect of the drugs. Ro10-5824 (0.3-3 mg/kg) increased the success rate in the difficult trial, potentiated the effect of lurasidone, and reversed the cognitive impairment induced by clozapine. Interestingly, the co-administration of L-745,870 with lurasidone decreased the success rate in the difficult trial, whereas the single administration of L-745,870 had no effect. These results suggest that activation of the dopamine D4 receptor may improve executive function, whereas concomitant blockade of dopamine D4 and D2 receptors may have the opposite effect. In addition to the other unique binding profiles of other monoamine receptors, the lack of affinity for the dopamine D4 receptor by lurasidone could also contribute, at least partly, to its cognitive-enhancing effect. PMID:24304719

  3. Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury

    PubMed Central

    Santos-Nogueira, Eva; López-Serrano, Clara; Hernández, Joaquim; Lago, Natalia; Astudillo, Alma M.; Balsinde, Jesús; Estivill-Torrús, Guillermo; de Fonseca, Fernando Rodriguez; Chun, Jerold

    2015-01-01

    Lysophosphatidic acid (LPA) is an extracellular lipid mediator involved in many physiological functions that signals through six known G-protein-coupled receptors (LPA1–LPA6). A wide range of LPA effects have been identified in the CNS, including neural progenitor cell physiology, astrocyte and microglia activation, neuronal cell death, axonal retraction, and development of neuropathic pain. However, little is known about the involvement of LPA in CNS pathologies. Herein, we demonstrate for the first time that LPA signaling via LPA1 contributes to secondary damage after spinal cord injury. LPA levels increase in the contused spinal cord parenchyma during the first 14 d. To model this potential contribution of LPA in the spinal cord, we injected LPA into the normal spinal cord, revealing that LPA induces microglia/macrophage activation and demyelination. Use of a selective LPA1 antagonist or mice lacking LPA1 linked receptor-mediated signaling to demyelination, which was in part mediated by microglia. Finally, we demonstrate that selective blockade of LPA1 after spinal cord injury results in reduced demyelination and improvement in locomotor recovery. Overall, these results support LPA–LPA1 signaling as a novel pathway that contributes to secondary damage after spinal cord contusion in mice and suggest that LPA1 antagonism might be useful for the treatment of acute spinal cord injury. SIGNIFICANCE STATEMENT This study reveals that LPA signaling via LPA receptor type 1 activation causes demyelination and functional deficits after spinal cord injury. PMID:26180199

  4. Contribution of metabotropic glutamate receptors to the depression of excitatory postsynaptic potentials during hypoxia.

    PubMed

    de Mendonça, A; Ribeiro, J A

    1997-12-01

    We tested the hypothesis that activation of metabotropic glutamate receptors (mGluR) might contribute to the depression of excitatory postsynaptic potentials during hypoxia. The experiments were performed on hippocampal slices taken from young (12-14 days old) Wistar rats. The depression induced by hypoxia (14 min) was not modified in the presence of either the non-selective mGluR antagonist (which blocks mainly group I and II mGluR), MCPG (500 microM) or the selective group III mGluR antagonist, MPPG (500 microM). However, in experiments performed in the presence of the selective adenosine A1 receptor antagonist, DPCPX (50 nM), part of the hypoxia-induced depression could be prevented by MPPG (500 microM). Activation of group III mGluR may contribute to the hypoxia-induced depression, but this contribution is only revealed when adenosine A1 receptors are blocked. PMID:9427348

  5. NMDA Receptor Activation and Calpain Contribute to Disruption of Dendritic Spines by the Stress Neuropeptide CRH

    PubMed Central

    Andres, Adrienne L.; Regev, Limor; Phi, Lucas; Seese, Ronald R.; Chen, Yuncai; Gall, Christine M.

    2013-01-01

    The complex effects of stress on learning and memory are mediated, in part, by stress-induced changes in the composition and structure of excitatory synapses. In the hippocampus, the effects of stress involve several factors including glucocorticoids and the stress-released neuropeptide corticotropin-releasing hormone (CRH), which influence the integrity of dendritic spines and the structure and function of the excitatory synapses they carry. CRH, at nanomolar, presumed-stress levels, rapidly abolishes short-term synaptic plasticity and destroys dendritic spines, yet the mechanisms for these effects are not fully understood. Here we tested the hypothesis that glutamate receptor-mediated processes, which shape synaptic structure and function, are engaged by CRH and contribute to spine destabilization. In cultured rat hippocampal neurons, CRH application reduced dendritic spine density in a time- and dose-dependent manner, and this action depended on the CRH receptor type 1. CRH-mediated spine loss required network activity and the activation of NMDA, but not of AMPA receptors; indeed GluR1-containing dendritic spines were resistant to CRH. Downstream of NMDA receptors, the calcium-dependent enzyme, calpain, was recruited, resulting in the breakdown of spine actin-interacting proteins including spectrin. Pharmacological approaches demonstrated that calpain recruitment contributed critically to CRH-induced spine loss. In conclusion, the stress hormone CRH co-opts mechanisms that contribute to the plasticity and integrity of excitatory synapses, leading to selective loss of dendritic spines. This spine loss might function as an adaptive mechanism preventing the consequences of adverse memories associated with severe stress. PMID:24155300

  6. NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH.

    PubMed

    Andres, Adrienne L; Regev, Limor; Phi, Lucas; Seese, Ronald R; Chen, Yuncai; Gall, Christine M; Baram, Tallie Z

    2013-10-23

    The complex effects of stress on learning and memory are mediated, in part, by stress-induced changes in the composition and structure of excitatory synapses. In the hippocampus, the effects of stress involve several factors including glucocorticoids and the stress-released neuropeptide corticotropin-releasing hormone (CRH), which influence the integrity of dendritic spines and the structure and function of the excitatory synapses they carry. CRH, at nanomolar, presumed-stress levels, rapidly abolishes short-term synaptic plasticity and destroys dendritic spines, yet the mechanisms for these effects are not fully understood. Here we tested the hypothesis that glutamate receptor-mediated processes, which shape synaptic structure and function, are engaged by CRH and contribute to spine destabilization. In cultured rat hippocampal neurons, CRH application reduced dendritic spine density in a time- and dose-dependent manner, and this action depended on the CRH receptor type 1. CRH-mediated spine loss required network activity and the activation of NMDA, but not of AMPA receptors; indeed GluR1-containing dendritic spines were resistant to CRH. Downstream of NMDA receptors, the calcium-dependent enzyme, calpain, was recruited, resulting in the breakdown of spine actin-interacting proteins including spectrin. Pharmacological approaches demonstrated that calpain recruitment contributed critically to CRH-induced spine loss. In conclusion, the stress hormone CRH co-opts mechanisms that contribute to the plasticity and integrity of excitatory synapses, leading to selective loss of dendritic spines. This spine loss might function as an adaptive mechanism preventing the consequences of adverse memories associated with severe stress. PMID:24155300

  7. Variation in the oxytocin receptor gene is associated with behavioral and neural correlates of empathic accuracy

    PubMed Central

    Laursen, Helle Ruff; Siebner, Hartwig Roman; Haren, Tina; Madsen, Kristoffer; Grønlund, Rikke; Hulme, Oliver; Henningsson, Susanne

    2014-01-01

    The neuromodulators oxytocin and serotonin have been implicated in regulating affective processes underlying empathy. Understanding this dependency, however, has been limited by a lack of objective metrics for measuring empathic performance. Here we employ a novel psychophysical method for measuring empathic performance that quantitatively measures the ability of subjects to decode the experience of another person's pain. In 50 female subjects, we acquired functional magnetic resonance imaging data as they were exposed to a target subject experiencing variable degrees of pain, whilst performing an irrelevant attention-demanding task. We investigated the effect of variation in the oxytocin receptor gene (OXTR) and the serotonin transporter gene (SLC6A4) on the psychophysical and neurometric variability associated with empathic performance. The OXTR rs2268498 and rs53576 polymorphisms, but not the SLC6A4 5-HTTLPR, were associated with significant differences in empathic accuracy, with CC- and AA-carriers, respectively, displaying higher empathic accuracy. For OXTR rs2268498 there was also a genotype difference in the correlation between empathic accuracy and activity in the superior temporal sulcus (STS). In OXTR rs2268498 CC-carriers, high empathic accuracy was associated with stronger responsiveness of the right STS to the observed pain. Together, the results show that genetic variation in the OXTR has significant influence on empathic accuracy and that this may be linked to variable responsivity of the STS. PMID:25538588

  8. Genetic contributions to avoidance-based decisions: striatal D2 receptor polymorphisms.

    PubMed

    Frank, M J; Hutchison, K

    2009-11-24

    Individuals differ in their tendencies to seek positive decision outcomes or to avoid negative ones. At the neurobiological level, our model suggests that phasic changes in dopamine support learning to reinforce good decisions via striatal D1 receptors, and to avoid maladaptive choices via striatal D2 receptors. Accordingly, in a previous study individual differences in positive and negative learning were strongly modulated by two genetic polymorphisms factors related to striatal D1 and D2 function, respectively. Nevertheless, whereas the role for dopamine in positive learning is relatively well accepted, that in learning to avoid negative outcomes is more controversial. Here we further explore D2-receptor-related genetic contributions to probabilistic avoidance in humans, in light of recent data showing that particular DRD2 polymorphisms are associated with functional modulation of receptor expression [Zhang Y, Bertolino A, Fazio L, Blasi G, Rampino A, Romano R, Lee M-LT, Xiao T, Papp A, Wang D, Sadée W (2007) Polymorphisms in human dopamine d2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc Natl Acad Sci U S A 104(51):20552-20557]. We find that a promoter polymorphism rs12364283 associated with transcription and D2 receptor density was strongly and selectively predictive of avoidance-based decisions. Two further polymorphisms (rs2283265 and rs1076560) associated with relatively reduced presynaptic relative to postsynaptic D2 receptor expression were predictive of relative impairments in negative compared to positive decisions. These previously undocumented effects of DRD2 polymorphisms were largely independent of those we reported previously for the C957T polymorphism (rs6277) associated with striatal D2 density. In contrast, effects of the commonly studied Taq1A polymorphism on reinforcement-based decisions were due to indirect association with C957T. Taken together these findings suggest multiple D2-dependent

  9. A cross talk between class A scavenger receptor and receptor for advanced glycation end-products contributes to diabetic retinopathy.

    PubMed

    Ma, Ke; Xu, Yiming; Wang, Chenchen; Li, Nan; Li, Kexue; Zhang, Yan; Li, Xiaoyu; Yang, Qing; Zhang, Hanwen; Zhu, Xudong; Bai, Hui; Ben, Jingjing; Ding, Qingqing; Li, Keran; Jiang, Qin; Xu, Yong; Chen, Qi

    2014-12-15

    In response to hyperglycemia in patients with diabetes, many signaling pathways contribute to the pathogenesis of diabetic complications, including diabetic retinopathy (DR). Excessive production of inflammatory mediators plays an important role in this process. Amadori-glycated albumin, one of the major forms of advanced glycated end-products, has been implicated in DR by inducing inflammatory responses in microglia/macrophages. Our goal was to delineate the potential cross talk between class A scavenger receptor (SR-A) and the receptor for advanced glycated end-product (RAGE) in the context of DR. We show here that SR-A ablation caused an exacerbated form of DR in streptozotocin-injected C57BL/6J mice as evidenced by fundus imaging and electroretinography. Immunohistochemical staining and RT-PCR assay indicated that there was augmented activation of proinflammatory macrophages with upregulated synthesis of proinflammatory mediators in the retina in Sr-a(-/-) mice. Overexpression of SR-A suppressed RAGE-induced mitogen-activated protein kinase (MAPK) signaling, whereas RAGE activation in macrophages favored a proinflammatory (M1) phenotype in the absence of SR-A. Mechanistic analysis on bone marrow-derived macrophages and HEK293 cell line revealed that SR-A interacted with and inhibited the phosphorylation of mitogen-activated protein kinase kinase 7, the major kinase in the RAGE-MAPK-NF-κB signaling, thereby leading to diminished secretion of proinflammatory cytokines. Our findings suggest that the antagonism between SR-A and RAGE contributes to the pathogenesis of DR by nurturing a disease-prone macrophage phenotype. Therefore, specific agonist that boosts SR-A signaling could potentially provide benefits in the prevention and/or intervention of DR. PMID:25352436

  10. Tumor Necrosis Factor Receptor 2: Its Contribution to Acute Cellular Rejection and Clear Cell Renal Carcinoma

    PubMed Central

    Wang, Jun; Al-Lamki, Rafia S.

    2013-01-01

    Tumor necrosis factor receptor 2 (TNFR2) is a type I transmembrane glycoprotein and one of the two receptors that orchestrate the complex biological functions of tumor necrosis factor (TNF, also designed TNF-α). Accumulating experimental evidence suggests that TNFR2 plays an important role in renal disorders associated with acute cellular rejection and clear cell renal carcinoma but its exact role in these settings is still not completely understood. This papers reviews the factors that may mediate TNFR2 induction in acute cellular rejection and clear cell renal carcinoma and its contribution to these conditions and discusses its therapeutic implications. A greater understanding of the function of TNFR2 may lead to the development of new anti-TNF drugs. PMID:24350291

  11. Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

    PubMed Central

    Zhang, Huiyun; Zeng, Xiaoning; He, Shaoheng

    2014-01-01

    Protease activated receptors (PARs) have been recognized as a distinctive four-member family of seven transmembrane G protein-coupled receptors (GPCRs) that can be cleaved by certain serine proteases. In recent years, there has been considerable interest in the role of PARs in allergic inflammation, the fundamental pathologic changes of allergy, but the potential roles of PARs in allergy remain obscure. Since many of these proteases are produced and actively involved in the pathologic process of inflammation including exudation of plasma components, inflammatory cell infiltration, and tissue damage and repair, PARs appear to make important contribution to allergy. The aim of the present review is to summarize the expression of PARs in inflammatory and structural cells, the influence of agonists or antagonists of PARs on cell behavior, and the involvement of PARs in allergic disorders, which will help us to better understand the roles of serine proteases and PARs in allergy. PMID:24876677

  12. Metabotropic Glutamate Receptor-1 Contributes to Progression in Triple Negative Breast Cancer

    PubMed Central

    Banda, Malathi; Speyer, Cecilia L.; Semma, Sara N.; Osuala, Kingsley O.; Kounalakis, Nicole; Torres Torres, Keila E.; Barnard, Nicola J.; Kim, Hyunjin J.; Sloane, Bonnie F.; Miller, Fred R.; Goydos, James S.; Gorski, David H.

    2014-01-01

    TNBC is an aggressive breast cancer subtype that does not express hormone receptors (estrogen and progesterone receptors, ER and PR) or amplified human epidermal growth factor receptor type 2 (HER2), and there currently exist no targeted therapies effective against it. Consequently, finding new molecular targets in triple negative breast cancer (TNBC) is critical to improving patient outcomes. Previously, we have detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in TNBC and observed that targeting glutamatergic signaling inhibits TNBC growth both in vitro and in vivo. In this study, we explored how mGluR1 contributes to TNBC progression, using the isogenic MCF10 progression series, which models breast carcinogenesis from nontransformed epithelium to malignant basal-like breast cancer. We observed that mGluR1 is expressed in human breast cancer and that in MCF10A cells, which model nontransformed mammary epithelium, but not in MCF10AT1 cells, which model atypical ductal hyperplasia, mGluR1 overexpression results in increased proliferation, anchorage-independent growth, and invasiveness. In contrast, mGluR1 knockdown results in a decrease in these activities in malignant MCF10CA1d cells. Similarly, pharmacologic inhibition of glutamatergic signaling in MCF10CA1d cells results in a decrease in proliferation and anchorage-independent growth. Finally, transduction of MCF10AT1 cells, which express c-Ha-ras, using a lentiviral construct expressing GRM1 results in transformation to carcinoma in 90% of resultant xenografts. We conclude that mGluR1 cooperates with other factors in hyperplastic mammary epithelium to contribute to TNBC progression and therefore propose that glutamatergic signaling represents a promising new molecular target for TNBC therapy. PMID:24404125

  13. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of nippostrongylus brasiliensis through induction of Th2 cytokines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and N...

  14. Contribution of opioid receptors on primary afferent versus sympathetic neurons to peripheral opioid analgesia.

    PubMed

    Zhou, L; Zhang, Q; Stein, C; Schäfer, M

    1998-08-01

    Opioid receptors are synthesized in dorsal root ganglia and transported into peripheral terminals of primary afferent neurons. Activation of such receptors results in antinociceptive effects that are most prominent in inflammation. In addition, opioid receptors located on sympathetic postganglionic neuron terminals may be involved in these effects. This study investigates the peripheral analgesic efficacy of the mu, delta and kappa receptor agonists [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin, [D-Pen2,5]-enkephalin and trans-(+/-)3, 4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e, the effective number of peripheral mu, delta and kappa receptors in relation to the development of inflammation and the contribution of sympathetic vs. sensory neurons by use of capsaicin and 6-hydroxydopamine, respectively. In Wistar rats with Freund's adjuvant-induced hindpaw inflammation, antinociceptive effects of intraplantar [D-Ala2,N-Me-Phe4,Gly-ol5]-enkephalin (1.0-32 microg), [D-Pen2,5]-enkephalin (10-100 microg) and trans-(+/-)3, 4-Dichloro-N-methyl-N-[2-(l-pyrrolidiny)-cyclohexyl]-benzeneace tam ide (10-100 microg) were evaluated by paw pressure test. These effects increased linearly between 6 and 24 hr, but did not change between 24 and 96 hr of inflammation, whereas the doses of the irreversible antagonists beta-funaltrexamine, [D-Ala2,Leu5,Cys6]enkephalin or (+/-)-(5beta,7a,8beta)-3, 4-dichloro-N-[3-methylene-2-oxo-8-(1-pyrrolidinyl)-1-oxaspir[4, 5]dec-7-yl]benzeneacetamide required to abolish the respective agonist effects increased between 12 and 96 hr. Pretreatment with capsaicin (30, 50, 70 mg/kg s.c. over 3 days) but not with 6-hydroxydopamine (75 mg/kg i.p. over 3 days) reversed the hyperalgesia in inflamed paws and almost abolished antinociceptive effects of all three agonists. These results suggest that the increased opioid agonist efficacy is due to an increased number of peripheral opioid receptors at later stages of inflammation and that

  15. Contribution of polycyclic aromatic hydrocarbon (PAH) sources to the urban environment: A comparison of receptor models.

    PubMed

    Teixeira, Elba Calesso; Agudelo-Castañeda, Dayana Milena; Mattiuzi, Camila Dalla Porta

    2015-12-15

    The aim of this study was to evaluate the contribution of the main emission sources of PAHs associated with PM2.5, in an urban area of the Rio Grande do Sul state. Source apportionment was conducted using both the US EPA Positive Matrix Factorization (PMF) model and the Chemical Mass Balance (CMB) model. The two models were compared to analyze the source contributions similarities and differences, their advantages and disadvantages. PM2.5 samples were collected continuously over 24h using a stacked filter unit at 3 sampling sites of the urban area of the Rio Grande do Sul state every 15days between 2006 and 2008. Both models identified the main emission sources of PAHs in PM2.5: vehicle fleet (diesel and gasoline), coal combustion, wood burning, and dust. Results indicated similar source contribution amongst the sampling sites, as expected because of the proximity amongst the sampling sites, which are under the influence of the same pollutants emitting sources. Moreover, differences were observed in obtained sources contributions for the same data set of each sampling site. The PMF model attributed a slightly greater amount of PAHs to the gasoline and diesel sources, while diesel contributed more in the CMB results. The results were comparable with previous works of the region and in accordance with the characteristics of the study area. Comparison between these receptor models, which contain different physical constraints, is important for understanding better PAH emissions sources in order to reduce air pollution. PMID:26298853

  16. Adipocyte glucocorticoid receptor has a minor contribution in adipose tissue growth.

    PubMed

    Desarzens, Sébastien; Faresse, Nourdine

    2016-07-01

    The glucocorticoids bind and activate both the glucocorticoid receptor (GR) as well as the mineralocorticoid receptor in adipocytes. Despite several studies to determine the function of these two receptors in mediating glucocorticoids effects, their relative contribution in adipose tissue expansion and obesity is unclear. To investigate the effect of GR in adipose tissue function, we generated an adipocyte-specific Gr-knockout mouse model (Gr(ad-ko)). These mice were submitted either to a standard diet or a high-fat high sucrose diet. We found that adipocyte-specific deletion of Gr did not affect body weight gain or adipose tissue formation and distribution. However, the lack of Gr in adipocyte promotes a diet-induced inflammation determined by higher pro-inflammatory genes expression and macrophage infiltration in the fat pads. Surprisingly, the adipose tissue inflammation in Gr(ad-ko) mice was not correlated with insulin resistance or dyslipidemia, but with disturbed glucose tolerance. Our data demonstrate that adipocyte-specific ablation of Gr in vivo may affect the adipose tissue function but not its expansion during a high calorie diet. PMID:27106108

  17. Mannose receptor contribution to Candida albicans phagocytosis by murine E-clone J774 macrophages.

    PubMed

    Porcaro, Isabelle; Vidal, Michel; Jouvert, Sylvie; Stahl, Philip D; Giaimis, Jean

    2003-08-01

    Mannoproteins, as the main constituents of the outer layer of yeast cell walls, are able to interact with phagocytic cells in an opsonin-independent manner through the mannose receptor (MR) and to induce yeast ingestion by the professional phagocytes. Moreover, the MR also mediates endocytosis of soluble ligands through clathrin-coated pits. Here, we studied some aspects of the interaction between the MR and Candida albicans using murine E-clone macrophages and the consequences on MR trafficking. Using a pull-down assay involving mixture E-clone macrophage detergent lysate with mannosylated Sepharose beads and glutaraldehyde-fixed, heat-killed (HK) C. albicans, we found that binding of solubilized MR to mannosylated particles occurred with characteristics similar to the receptor's cell-surface mannose-binding activity. We then demonstrated that MR expressed on E-clone macrophages contributed to phagocytosis of unopsonized, HK C. albicans and that yeast phagocytosis induced a decrease in MR endocytic activity without concomitant degradation of the receptor in the time lapse studied. PMID:12885937

  18. Melanocortin 4 receptor mutations contribute to the adaptation of cavefish to nutrient-poor conditions.

    PubMed

    Aspiras, Ariel C; Rohner, Nicolas; Martineau, Brian; Borowsky, Richard L; Tabin, Clifford J

    2015-08-01

    Despite recent advances in the understanding of morphological evolution, the genetic underpinnings of behavioral and physiological evolution remain largely unknown. Here, we study the metabolic changes that evolved in independently derived populations of the Mexican cavefish, Astyanax mexicanus. A hallmark of cave environments is scarcity of food. Cavefish populations rely almost entirely on sporadic food input from outside of the caves. To survive under these conditions, cavefish have evolved a range of adaptations, including starvation resistance and binge eating when food becomes available. The use of these adaptive strategies differs among independently derived cave populations. Although all cavefish populations tested lose weight more slowly than their surface conspecifics during restricted rations, only a subset of cavefish populations consume more food than their surface counterparts. A candidate gene-based screen led to the identification of coding mutations in conserved residues of the melanocortin 4 receptor (MC4R) gene, contributing to the insatiable appetite found in some populations of cavefish. Intriguingly, one of the mutated residues has been shown to be linked to obesity in humans. We demonstrate that the allele results in both reduced maximal response and reduced basal activity of the receptor in vitro. We further validate in vivo that the mutated allele contributes to elevated appetite, growth, and starvation resistance. The allele appears to be fixed in cave populations in which the overeating phenotype is present. The presence of the same allele in multiple caves appears to be due to selection from standing genetic variation present in surface populations. PMID:26170297

  19. Melanocortin 4 receptor mutations contribute to the adaptation of cavefish to nutrient-poor conditions

    PubMed Central

    Aspiras, Ariel C.; Rohner, Nicolas; Martineau, Brian; Borowsky, Richard L.; Tabin, Clifford J.

    2015-01-01

    Despite recent advances in the understanding of morphological evolution, the genetic underpinnings of behavioral and physiological evolution remain largely unknown. Here, we study the metabolic changes that evolved in independently derived populations of the Mexican cavefish, Astyanax mexicanus. A hallmark of cave environments is scarcity of food. Cavefish populations rely almost entirely on sporadic food input from outside of the caves. To survive under these conditions, cavefish have evolved a range of adaptations, including starvation resistance and binge eating when food becomes available. The use of these adaptive strategies differs among independently derived cave populations. Although all cavefish populations tested lose weight more slowly than their surface conspecifics during restricted rations, only a subset of cavefish populations consume more food than their surface counterparts. A candidate gene-based screen led to the identification of coding mutations in conserved residues of the melanocortin 4 receptor (MC4R) gene, contributing to the insatiable appetite found in some populations of cavefish. Intriguingly, one of the mutated residues has been shown to be linked to obesity in humans. We demonstrate that the allele results in both reduced maximal response and reduced basal activity of the receptor in vitro. We further validate in vivo that the mutated allele contributes to elevated appetite, growth, and starvation resistance. The allele appears to be fixed in cave populations in which the overeating phenotype is present. The presence of the same allele in multiple caves appears to be due to selection from standing genetic variation present in surface populations. PMID:26170297

  20. Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice.

    PubMed

    Miyazaki, Shinji; Hiraoka, Yuichi; Hidema, Shizu; Nishimori, Katsuhiko

    2016-04-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, difficulty in companionship, repetitive behaviors and restricted interests. Recent studies have shown amelioration of ASD symptoms by intranasal administration of oxytocin and demonstrated the association of polymorphisms in the oxytocin receptor (Oxtr) gene with ASD patients. Deficient pruning of synapses by microglial cells in the brain has been proposed as potential mechanism of ASD. Other researchers have shown specific activation of microglial cells in brain regions related to sociality in patients with ASD. Although the roles of Oxtr and microglia in ASD are in the spotlight, the relationship between them remains to be elucidated. In this study, we found abnormal activation of microglial cells and a reduction of postsynaptic density protein PSD95 expression in the Oxtr-deficient brain. Moreover, pharmacological inhibition of microglia during development can alter the expression of PSD95 and ameliorate abnormal mother-infant communication in Oxtr-deficient mice. Our results suggest that microglial abnormality is a potential mechanism of the development of Oxt/Oxtr mediated ASD-like phenotypes. PMID:26926566

  1. Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures.

    PubMed

    Iori, Valentina; Maroso, Mattia; Rizzi, Massimo; Iyer, Anand M; Vertemara, Roberta; Carli, Mirjana; Agresti, Alessandra; Antonelli, Antonella; Bianchi, Marco E; Aronica, Eleonora; Ravizza, Teresa; Vezzani, Annamaria

    2013-10-01

    Toll-like receptor 4 (TLR4) activation in neuron and astrocytes by High Mobility Group Box 1 (HMGB1) protein is a key mechanism of seizure generation. HMGB1 also activates the Receptor for Advanced Glycation Endproducts (RAGE), but it was unknown whether RAGE activation contributes to seizures or to HMGB1 proictogenic effects. We found that acute EEG seizures induced by 7ng intrahippocampal kainic acid (KA) were significantly reduced in Rage-/- mice relative to wild type (Wt) mice. The proictogenic effect of HMGB1 was decreased in Rage-/- mice, but less so, than in Tlr4-/- mice. In a mouse mesial temporal lobe epilepsy (mTLE) model, status epilepticus induced by 200ng intrahippocampal KA and the onset of the spontaneous epileptic activity were similar in Rage-/-, Tlr4-/- and Wt mice. However, the number of hippocampal paroxysmal episodes and their duration were both decreased in epileptic Rage-/- and Tlr4-/- mice vs Wt mice. All strains of epileptic mice displayed similar cognitive deficits in the novel object recognition test vs the corresponding control mice. CA1 neuronal cell loss was increased in epileptic Rage-/- vs epileptic Wt mice, while granule cell dispersion and doublecortin (DCX)-positive neurons were similarly affected. Notably, DCX neurons were preserved in epileptic Tlr4-/- mice. We did not find compensatory changes in HMGB1-related inflammatory signaling nor in glutamate receptor subunits in Rage-/- and Tlr4-/- naïve mice, except for ~20% NR2B subunit reduction in Rage-/- mice. RAGE was induced in neurons, astrocytes and microvessels in human and experimental mTLE hippocampi. We conclude that RAGE contributes to hyperexcitability underlying acute and chronic seizures, as well as to the proictogenic effects of HMGB1. RAGE and TLR4 play different roles in the neuropathologic sequelae developing after status epilepticus. These findings reveal new molecular mechanisms underlying seizures, cell loss and neurogenesis which involve inflammatory pathways

  2. Contribution of increased VEGF receptors to hypoxic changes in fetal ovine carotid artery contractile proteins.

    PubMed

    Adeoye, Olayemi O; Butler, Stacy M; Hubbell, Margaret C; Semotiuk, Andrew; Williams, James M; Pearce, William J

    2013-04-01

    Recent studies suggest that vascular endothelial growth factor (VEGF) can modulate smooth muscle phenotype and, consequently, the composition and function of arteries upstream from the microcirculation, where angiogenesis occurs. Given that hypoxia potently induces VEGF, the present study explores the hypothesis that, in fetal arteries, VEGF contributes to hypoxic vascular remodeling through changes in abundance, organization, and function of contractile proteins. Pregnant ewes were acclimatized at sea level or at altitude (3,820 m) for the final 110 days of gestation. Endothelium-denuded carotid arteries from full-term fetuses were used fresh or after 24 h of organ culture in a physiological concentration (3 ng/ml) of VEGF. After 110 days, hypoxia had no effect on VEGF abundance but markedly increased abundance of the Flk-1 (171%) and Flt-1 (786%) VEGF receptors. Hypoxia had no effect on smooth muscle α-actin (SMαA), decreased myosin light chain (MLC) kinase (MLCK), and increased 20-kDa regulatory MLC (MLC(20)) abundances. Hypoxia also increased MLCK-SMαA, MLC(20)-SMαA, and MLCK-MLC(20) colocalization. Compared with hypoxia, organ culture with VEGF produced the same pattern of changes in contractile protein abundance and colocalization. Effects of VEGF on colocalization were blocked by the VEGF receptor antagonists vatalanib (240 nM) and dasatinib (6.3 nM). Thus, through increases in VEGF receptor density, hypoxia can recruit VEGF to help mediate remodeling of fetal arteries upstream from the microcirculation. The results support the hypothesis that VEGF contributes to hypoxic vascular remodeling through changes in abundance, organization, and function of contractile proteins. PMID:23325408

  3. Nicotinic acetylcholine receptors contribute to learning-induced metaplasticity in the hippocampus.

    PubMed

    Becker, Benjamin; Klein, Eva M; Striepens, Nadine; Mihov, Yoan; Schlaepfer, Thomas E; Reul, Juergen; Goossens, Liesbet; Schruers, Koen; Kendrick, Keith M; Hurlemann, René

    2013-07-01

    Hippocampal learning is thought to induce metaplasticity, which can facilitate subsequent learning. Administered at single low doses, the N-methyl-d-aspartate-type glutamate receptor antagonist memantine predominantly blocks α7 nicotinic acetylcholine receptors (α7 nAChRs). Placebo-controlled administration of a single low dose of memantine in a pharmaco-fMRI experiment may thus help characterize the role of α7 nAChRs in hippocampal metaplasticity. We hypothesized that if α7 nAChRs contribute to learning-induced metaplasticity in the hippocampus, blockade of these receptors with low-dose memantine would selectively interfere with a facilitation of subsequent learning without impairing hippocampal learning per se. To specifically test this hypothesis, we devised a randomized controlled trial in which healthy volunteers were administered a 20-mg single oral dose of memantine or placebo and scanned on three subsequent runs of a hippocampal learning task. Our results indicate no discrepancies in behavioral learning between low-dose memantine- and placebo-treated participants in the first and second run of this task. In the third run, however, only the placebo-treated group showed facilitated behavioral learning, an effect paralleled by decreased neural responses in the hippocampal cornu ammonis region. Our findings suggest that blockade of α7 nAChRs selectively interfered with a learning-induced facilitation of subsequent learning while leaving unimpaired hippocampal learning per se. Taken together, our results provide support for a relevant contribution of α7 nAChRs to learning-associated metaplasticity in the hippocampus. PMID:23469888

  4. Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation.

    PubMed

    Jennewein, Carla; Sowa, Ralf; Faber, Anne C; Dildey, Madlen; von Knethen, Andreas; Meybohm, Patrick; Scheller, Bertram; Dröse, Stefan; Zacharowski, Kai

    2015-11-01

    Nerve injury-induced protein (Ninjurin [Ninj]) 1 is an adhesion molecule originally identified in Schwann cells after nerve injury, whereas it is also expressed in leukocytes, epithelium, endothelium, and various organs, and is induced under inflammatory conditions. Its contribution to inflammation was so far restricted to the nervous system and exclusively attributed to its role during leukocyte migration. We hypothesized a proinflammatory role for Ninj1 also outside the nervous system. To elucidate its impact during inflammation, we analyzed expression levels and its contribution to inflammation in septic mice and studied its effect on inflammatory signaling in vitro. The effect on inflammation was analyzed by genetic (only in vitro) and pharmacologic repression in septic mice (cecal ligation and puncture) and cell culture, respectively. Repression of Ninj1 by an inhibitory peptide or small interfering RNA attenuated LPS-triggered inflammation in macrophages and endothelial cells by modulating p38 phosphorylation and activator protein-1 activation. Inhibition of Ninj1 in septic mice reduced systemic and pulmonary inflammation as well as organ damage, and ameliorated survival after 24 hours. Ninj1 is elevated under inflammatory conditions and contributes to inflammation not only by mediating leukocyte migration, but also by modulating Toll-like receptor 4-dependent expression of inflammatory mediators. We assume that, owing to both mechanisms, inhibition reduces systemic inflammation and organ damage in septic mice. Our data contribute to a better understanding of the complex inflammatory mechanisms and add a novel therapeutic target for inflammatory conditions such as sepsis. PMID:25860173

  5. A Bayesian Multivariate Receptor Model for Estimating Source Contributions to Particulate Matter Pollution using National Databases

    PubMed Central

    Hackstadt, Amber J.; Peng, Roger D.

    2014-01-01

    Summary Time series studies have suggested that air pollution can negatively impact health. These studies have typically focused on the total mass of fine particulate matter air pollution or the individual chemical constituents that contribute to it, and not source-specific contributions to air pollution. Source-specific contribution estimates are useful from a regulatory standpoint by allowing regulators to focus limited resources on reducing emissions from sources that are major contributors to air pollution and are also desired when estimating source-specific health effects. However, researchers often lack direct observations of the emissions at the source level. We propose a Bayesian multivariate receptor model to infer information about source contributions from ambient air pollution measurements. The proposed model incorporates information from national databases containing data on both the composition of source emissions and the amount of emissions from known sources of air pollution. The proposed model is used to perform source apportionment analyses for two distinct locations in the United States (Boston, Massachusetts and Phoenix, Arizona). Our results mirror previous source apportionment analyses that did not utilize the information from national databases and provide additional information about uncertainty that is relevant to the estimation of health effects. PMID:25309119

  6. Assessment of transboundary ozone contribution toward South Korea using multiple source-receptor modeling techniques

    NASA Astrophysics Data System (ADS)

    Choi, Ki-Chul; Lee, Jong-Jae; Bae, Chang Han; Kim, Cheol-Hee; Kim, Soontae; Chang, Lim-Seok; Ban, Soo-Jin; Lee, Suk-Jo; Kim, Jongchoon; Woo, Jung-Hun

    2014-08-01

    Ozone concentrations in East Asia were simulated using the Community Multi-scale Air Quality (CMAQ) model, and its source contributions were estimated by multiple source-receptor modeling techniques. To study relationships between ozone concentrations and precursor emission sources, three approaches were applied to four months (January, April, July, and October 2009) to represent seasonal characteristics and compare results, with a particular focus on South Korea. Brute force (BF) is a traditional sensitivity analysis method used to estimate model output response to an input change. The high-order decoupled direct method (HDDM), a computational method, is an efficient and accurate alternative to the BF method for sensitivity. The Ozone and Particulate Precursor Tagging Methodology (OPTM) provides contribution information quantified by tracking emissions from selected sources throughout the simulation period. The approaches generally show that most of the receptor regions were substantially influenced by emissions from central China, which is the largest anthropogenic emissions source region in East Asia. Local emissions were still major contributors, especially South Korea and Japan during July 2009. On the other hand, a case study of maximum 8-h ozone concentrations derived from CMAQ-OPTM on April 9 in South Korea shows that the NOx and VOCs emissions from China contributed approximately 82% and 91%, respectively, to maximum 8-h ozone in Region 4 (South Korea) without boundary inflow, which indicates that Chinese emissions are the dominant contributor in this episode. A comparison study of the three approaches shows that HDDM tends to estimate biogenic source contributions lower than that from OPTM in China but similar to OPTM in South Korea and Japan. When comparing the BF method and HDDM, the sensitivity results show a reasonably good agreement during a given period. The location- and time-dependent maximum 8-h ozone isopleths over South Korea as a receptor

  7. Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa.

    PubMed

    Acevedo, Summer F; Valencia, Celeste; Lutter, Michael; McAdams, Carrie J

    2015-08-30

    Oxytocin is a peptide hormone important for social behavior and differences in psychological traits have been associated with variants of the oxytocin receptor gene in healthy people. We examined whether single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene (OXTR) correlated with clinical symptoms in women with anorexia nervosa, bulimia nervosa, and healthy comparison (HC) women. Subjects completed clinical assessments and provided DNA for analysis. Subjects were divided into four groups: HC, subjects currently with anorexia nervosa (AN-C), subjects with a history of anorexia nervosa but in long-term weight recovery (AN-WR), and subjects with bulimia nervosa (BN). Five SNPs of the oxytocin receptor were examined. Minor allele carriers showed greater severity in most of the psychiatric symptoms. Importantly, the combination of having had anorexia and carrying either of the A alleles for two SNPS in the OXTR gene (rs53576, rs2254298) was associated with increased severity specifically for ED symptoms including cognitions and behaviors associated both with eating and appearance. A review of psychosocial data related to the OXTR polymorphisms examined is included in the discussion. OXTR polymorphisms may be a useful intermediate endophenotype to consider in the treatment of patients with anorexia nervosa. PMID:26106053

  8. Ischaemic skeletal muscle hyperaemia in the anaesthetized cat: no contribution of A2A adenosine receptors.

    PubMed Central

    Poucher, S M

    1997-01-01

    1. The present study investigated the contribution of the A2A adenosine receptor subtype to the functional hyperaemia response evoked by muscle contraction in anaesthetized cats when muscle blood flow was limited. 2. Application of a stenosis reduced the hindlimb blood flow at rest from 9.67 +/- 1.80 to 5.53 +/- 0.91 ml min(-1) (kg body mass)(-1) and during muscle contraction from 36.80 +/- 2.55 to 11.11 +/- 1.19 ml min(-1) (kg body mass)(-1) (P < 0.001). The force produced by the extensor digitorum longus and tibialis anterior (EDL-TA) muscle groups was also reduced, from 9.66 +/- 0.56 to 4.10 +/- 0.4 N (kg muscle mass)(-1) (P < 0.01). 3. The selective A2A adenosine receptor antagonist ZM241385 (3 mg kg(-1), I.V.) had no effect upon the hindlimb vascular conductance or muscle contraction responses in the presence of the flow-limiting stenosis. 4. In contrast, in the absence of the flow restriction the vascular conductance response was reduced by 27.5 +/- 5.0% (P < 0.05), whilst the isometric force produced by the EDL-TA muscle group was unaffected (pre- vs. post-contraction, 5.8 +/- 0.8 vs. 4.6 +/- 1.0 N (kg muscle mass)(-1) contraction). Oxygen consumption by the contracting hindlimb muscles was maintained (1.71 +/- 0.25 vs. 1.69 +/- 0.26 ml min(-1) (kg body mass)(-1)) by an increase in the oxygen extraction (51.9 +/- 4.9 vs. 66.2 +/- 6.1%; P< 0.01). 5. These results confirm previous data showing that adenosine, acting at the A2A receptor subtype, can contribute up to 30% of the functional hyperaemia response in the hindlimb of anaesthetized cats under free flow conditions. However, when blood flow is limited by a stenosis, antagonism of the A2A adenosine receptor does not affect functional hyperaemia. Images Figure 1 PMID:9097944

  9. The nuclear receptors pregnane X receptor and constitutive androstane receptor contribute to the impact of fipronil on hepatic gene expression linked to thyroid hormone metabolism.

    PubMed

    Roques, Béatrice B; Leghait, Julien; Lacroix, Marlène Z; Lasserre, Frédéric; Pineau, Thierry; Viguié, Catherine; Martin, Pascal G P

    2013-10-01

    Fipronil is described as a thyroid disruptor in rat. Based on the hypothesis that this results from a perturbation of hepatic thyroid hormone metabolism, our goal was to investigate the pathways involved in fipronil-induced liver gene expression regulations. First, we performed a microarray screening in the liver of rats treated with fipronil or vehicle. Fipronil treatment led to the upregulation of several genes involved in the metabolism of xenobiotics, including the cytochrome P450 Cyp2b1, Cyp2b2 and Cyp3a1, the carboxylesterases Ces2 and Ces6, the phase II enzymes Ugt1a1, Sult1b1 and Gsta2, and the membrane transporters Abcc2, Abcc3, Abcg5, Abcg8, Slco1a1 and Slco1a4. Based on a large overlap with the target genes of constitutive androstane receptor (CAR) and pregnane X receptor (PXR), we postulated that these two nuclear receptors are involved in mediating the effects of fipronil on liver gene expression in rodents. We controlled that liver gene expression changes induced by fipronil were generally reproduced in mice, and then studied the effects of fipronil in wild-type, CAR- and PXR-deficient mice. For most of the genes studied, the gene expression modulations were abolished in the liver of PXR-deficient mice and were reduced in the liver of CAR-deficient mice. However, CAR and PXR activation in mouse liver was not associated with a marked increase of thyroid hormone clearance, as observed in rat. Nevertheless, our data clearly indicate that PXR and CAR are key modulators of the hepatic gene expression profile following fipronil treatment which, in rats, may contribute to increase thyroid hormone clearance. PMID:23962444

  10. Oxytocin and the oxytocin receptor underlie intra-strain, but not inter-strain, social recognition

    PubMed Central

    Macbeth, Abbe H.; Lee, Heon-Jin; Edds, Jennifer; Young, W. Scott

    2009-01-01

    We studied three lines of oxytocin (Oxt) and oxytocin receptor (Oxtr) knockout (KO) male mice (Oxt−/−, total Oxtr−/−, and partial-forebrain Oxtr (OxtrFB/FB)) with established deficits in social recognition to further refine our understanding of their deficits with regard to stimulus female's strain. We used a modified social discrimination paradigm in which subjects are singly housed only for the duration of the test. Additionally, stimulus females are singly-housed throughout testing and are presented within corrals for rapid comparison of investigation by subject males. Wildtype (WT) males from all three lines discriminated between familiar and novel females of three different strains (C57BL/6, Balb/c, Swiss-Webster). No KO males discriminated between familiar and novel Balb/c or C57BL/6 females. Male Oxt−/− and Oxtr−/− mice, but not OxtrFB/FB mice, discriminated between familiar and novel Swiss-Webster females. As this might indicate a global deficit in individual recognition for OxtrFB/FB males, we examined their ability to discriminate between females from different strains and compared performance with Oxtr−/− males. WT and KO males from both lines were able to distinguish between familiar and novel females from different strains, indicating the social recognition deficit is not universal. Instead, we hypothesize that the Oxtr is involved in “fine” intra-strain recognition, but is less important in “broad” inter-strain recognition. We also present the novel finding of decreased investigation across tests, which is likely an artifact of repeated testing and not due to stimulus female's strain or age of subject males. PMID:19531157

  11. Contributions of Unique Intracellular Domains to Switchlike Biosensing by Toll-like Receptor 4*

    PubMed Central

    Daringer, Nichole M.; Schwarz, Kelly A.; Leonard, Joshua N.

    2015-01-01

    Toll-like receptors (TLRs) mediate immune recognition of both microbial infections and tissue damage. Aberrant TLR signaling promotes disease; thus, understanding the regulation of TLR signaling is of medical relevance. Although downstream mediators of TLR signaling have been identified, the detailed mechanism by which ligand binding-mediated dimerization induces downstream signaling remains poorly understood. Here, we investigate this question for TLR4, which mediates responsiveness to bacterial LPS and drives inflammatory disease. TLR4 exhibits structural and functional features that are unique among TLRs, including responsiveness to a wide variety of ligands. However, the connection between these structural features and the regulation of signaling is not clear. Here, we investigated how the unique intracellular structures of TLR4 contribute to receptor signaling. Key conclusions include the following. 1) The unique intracellular linker of TLR4 is important for achieving LPS-inducible signaling via Toll/IL-1 receptor (TIR) domain-containing adapter-inducing interferon-β (TRIF) but less so for signaling via myeloid differentiation primary response 88 (MyD88). 2) Membrane-bound TLR4 TIR domains were sufficient to induce signaling. However, introducing long, flexible intracellular linkers neither induced constitutive signaling nor ablated LPS-inducible signaling. Thus, the initiation of TLR4 signaling is regulated by a mechanism that does not require tight geometric constraints. Together, these observations necessitate refining the model of TLR4 signal initiation. We hypothesize that TLR4 may interact with an inhibitory partner in the absence of ligand, via both TIR and extracellular domains of TLR4. In this speculative model, ligand binding induces dissociation of the inhibitory partner, triggering spontaneous, switchlike TIR domain homodimerization to initiate downstream signaling. PMID:25694428

  12. The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis.

    PubMed

    Fuller, Miles; Priyadarshini, Medha; Gibbons, Sean M; Angueira, Anthony R; Brodsky, Michael; Hayes, M Geoffrey; Kovatcheva-Datchary, Petia; Bäckhed, Fredrik; Gilbert, Jack A; Lowe, William L; Layden, Brian T

    2015-11-15

    The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (WT) mice the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short-chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein-coupled receptors (GPCRs) such as free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene (Ffar2) expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Together, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiome contribute to gestational glucose homeostasis. PMID:26394664

  13. Contribution of β-adrenergic receptors to exercise-induced bronchodilatation in healthy humans.

    PubMed

    Antonelli, Andrea; Torchio, Roberto; Bertolaccini, Luca; Terzi, Alberto; Rolfo, Fabrizio; Agostoni, Piergiuseppe; Gulotta, Carlo; Brusasco, Vito; Pellegrino, Riccardo

    2012-10-15

    Exercise in healthy subjects is usually associated with progressive bronchodilatation. Though the decrease in vagal tone is deemed to be the main underlying mechanism, activation of bronchial β(2)-receptors may constitute an additional cause. To examine the contribution of β(2)-adrenergic receptors to bronchodilatation during exercise in healthy humans, we studied 15 healthy male volunteers during maximum exercise test at control conditions and after a non-selective β-adrenergic blocker (carvedilol 12.5mg twice a day until heart rate decreased at least by 10beats/min) and inhaled β(2)-agonist (albuterol 400μg). Airway caliber was estimated from the partial flow at 40% of control forced vital capacity (V˙(part40)) and its changes during exercise from the slope of linear regression analysis of V˙(part40) values against the corresponding minute ventilation during maximal exercise until exhaustion. At control, V˙(part40) increased progressively and significantly with exercise. After albuterol, resting V˙(part40) was significantly larger than at control increased but did not further increase during exercise. After carvedilol, V˙(part40) was similar to control but its increase with exercise was significantly attenuated. These findings suggest that β(2)-adrenergic system plays a major role in exercise-induced bronchodilation in healthy subjects. PMID:22842007

  14. Leptin receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake.

    PubMed

    Alhadeff, Amber L; Hayes, Matthew R; Grill, Harvey J

    2014-12-01

    Pontine parabrachial nucleus (PBN) neurons integrate visceral, oral, and other sensory information, playing an integral role in the neural control of feeding. Current experiments probed whether lateral PBN (lPBN) leptin receptor (LepRb) signaling contributes to this function. Intra-lPBN leptin microinjection significantly reduced cumulative chow intake, average meal size, and body weight in rats, independent of effects on locomotor activity or gastric emptying. In contrast to the effects observed following LepRb activation in other nuclei, lPBN LepRb stimulation did not affect progressive ratio responding for sucrose reward or conditioned place preference for a palatable food. Collectively, results suggest that lPBN LepRb activation reduces food intake by modulating the neural processing of meal size/satiation signaling, and highlight the lPBN as a novel site of action for leptin-mediated food intake control. PMID:25298514

  15. Cortical Metabotropic Glutamate Receptors Contribute to Habituation of a Simple Odor-Evoked Behavior

    PubMed Central

    Best, Aaron R.; Thompson, Jason V.; Fletcher, Max L.; Wilson, Donald A.

    2008-01-01

    Defining the circuits that are involved in production and cessation of specific behaviors is an ultimate goal of neuroscience. Short-term behavioral habituation is the response decrement observed in many behaviors that occurs during repeated presentation of non-reinforced stimuli. Within a number of invertebrate models of short-term behavioral habituation, depression of a defined synapse has been implicated as the mechanism. However, the synaptic mechanisms of short-term behavioral habituation have not been identified within mammals. We have shown previously that a presynaptic metabotropic glutamate receptor (mGluR)-dependent depression of synapses formed by olfactory bulb afferents to the piriform (olfactory) cortex significantly contributes to adaptation of cortical odor responses. Here we show that blockade of mGluRs within the olfactory cortex of awake, behaving rats diminishes habituation of a simple odor-induced behavior, strongly implicating a central mechanism for sensory gating in olfaction. PMID:15758159

  16. Hyperactivation of D1 and A2A receptors contributes to cognitive dysfunction in Huntington's disease.

    PubMed

    Tyebji, Shiraz; Saavedra, Ana; Canas, Paula M; Pliassova, Anna; Delgado-García, José M; Alberch, Jordi; Cunha, Rodrigo A; Gruart, Agnès; Pérez-Navarro, Esther

    2015-02-01

    Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease. PMID:25449908

  17. Contribution of programmed cell death receptor (PD)-1 to Kupffer cell dysfunction in murine polymicrobial sepsis.

    PubMed

    Wang, Fei; Huang, Xin; Chung, Chun-Shiang; Chen, Yaping; Hutchins, Noelle A; Ayala, Alfred

    2016-08-01

    Recent studies suggest that coinhibitory receptors appear to be important in contributing sepsis-induced immunosuppression. Our laboratory reported that mice deficient in programmed cell death receptor (PD)-1 have increased bacterial clearance and improved survival in experimental sepsis induced by cecal ligation and puncture (CLP). In response to infection, the liver clears the blood of bacteria and produces cytokines. Kupffer cells, the resident macrophages in the liver, are strategically situated to perform the above functions. However, it is not known if PD-1 expression on Kupffer cells is altered by septic stimuli, let alone if PD-1 ligation contributes to the altered microbial handling seen. Here we report that PD-1 is significantly upregulated on Kupffer cells during sepsis. PD-1-deficient septic mouse Kupffer cells displayed markedly enhanced phagocytosis and restoration of the expression of major histocompatibility complex II and CD86, but reduced CD80 expression compared with septic wild-type (WT) mouse Kupffer cells. In response to ex vivo LPS stimulation, the cytokine productive capacity of Kupffer cells derived from PD-1-/- CLP mice exhibited a marked, albeit partial, restoration of the release of IL-6, IL-12, IL-1β, monocyte chemoattractant protein-1, and IL-10 compared with septic WT mouse Kupffer cells. In addition, PD-1 gene deficiency decreased LPS-induced apoptosis of septic Kupffer cells, as indicated by decreased levels of cleaved caspase-3 and reduced terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells. Exploring the signal pathways involved, we found that, after ex vivo LPS stimulation, septic PD-1-/- mouse Kupffer cells exhibited an increased Akt phosphorylation and a reduced p38 phosphorylation compared with septic WT mouse Kupffer cells. Together, these results indicate that PD-1 appears to play an important role in regulating the development of Kupffer cell dysfunction seen in sepsis. PMID:27288425

  18. CONTRIBUTION OF PROTEASE-ACTIVATED RECEPTOR 1 IN STATUS EPILEPTICUS-INDUCED EPILEPTOGENESIS

    PubMed Central

    Isaev, D.; Lushnikova, I.; Lunko, O.; Zapukhliak, O.; Maximyuk, O.; Romanov, A.; Skibo, G.G.; Tian, C.; Holmes, G.L.; Isaeva, E.

    2015-01-01

    Clinical observations and studies on different animal models of acquired epilepsy consistently demonstrate that blood-brain barrier (BBB) leakage can be an important risk factor for developing recurrent seizures. However, the involved signaling pathways remain largely unclear. Given the important role of thrombin and its major receptor in the brain, protease-activated receptor 1 (PAR1), in the pathophysiology of neurological injury, we hypothesized that PAR1 may contribute to status epilepticus (SE)-induced epileptogenesis and that its inhibition shortly after SE will have neuroprotective and antiepileptogenic effects. Adult rats subjected to lithium-pilocarpine SE were administrated SCH79797 (a PAR1 selective antagonist) after SE termination. Thrombin and PAR1 levels and neuronal cell survival were evaluated 48 hr following SE. The effect of PAR1 inhibition on animal survival, interictal spikes (IIS) and electrographic seizures during the first two weeks after SE and behavioral seizures during the chronic period were evaluated. SE resulted in a high mortality rate and incidence of IIS and seizures in the surviving animals. There was a marked increase in thrombin, decrease in PAR1 immunoreactivity and hippocampal cell loss in the SE-treated rats. Inhibition of PAR1 following SE resulted in a decrease in mortality and morbidity, increase in neuronal cell survival in the hippocampus and suppression of IIS, electrographic and behavioral seizures following SE. These data suggest that the PAR1 signaling pathway contributes to epileptogenesis following SE. Because breakdown of the BBB occurs frequently in brain injuries, PAR1 inhibition may have beneficial effects in a variety of acquired injuries leading to epilepsy. PMID:25843668

  19. Contribution of cone photoreceptors and post-receptoral mechanisms to the human photopic electroretinogram

    PubMed Central

    Friedburg, C; Allen, C P; Mason, P J; Lamb, T D

    2004-01-01

    We recorded the electroretinogram (ERG) from human subjects with normal vision, using ganzfeld stimulation in the presence of rod-suppressing blue background light. In families of responses to flashes of increasing intensity, we investigated features of both receptoral and post-receptoral origin. Firstly, we found that the oscillatory potentials (OPs, that have long been known to be post-receptoral) exhibited a time course that was invariant over a range of bright flash intensities. Secondly, we found that the photopic b-wave (which probably originates in cone ON bipolar cells) was most pronounced after test flashes of around 20 Td s, and could be suppressed either by increasing the test flash intensity or by applying a second flash after the test flash. We obtained estimates of the time course of the cone photoreceptor response using the paired-flash technique, in which an intense ‘probe’ flash was delivered at different times after a test flash. The response to the probe flash was recorded and, its amplitude was measured at early times after the probe flash. Estimates obtained in this way were of normalized amplitude, but could be scaled to an absolute amplitude by making an assumption about the level of probe-flash response that corresponded to complete suppression of photoreceptor current. For moderately bright test flashes the estimated cone photoreceptor response at early times coincided closely with the a-wave of the test flash ERG. However, the maximal size of this estimated response accounted for only about 70% of the peak a-wave amplitude in the case of bright flashes, and for an even smaller proportion after flashes of lower intensity, and we take this to indicate the existence of a third substantial post-receptoral contribution to the a-wave. For dim flashes, the time-to-peak of the cone response was around 15–20 ms, and for saturating flashes the dominant time constant of recovery was about 18 ms. The intensity dependence of the estimated cone

  20. Differential Contributions of Olfactory Receptor Neurons in a Drosophila Olfactory Circuit.

    PubMed

    Newquist, Gunnar; Novenschi, Alexandra; Kohler, Donovan; Mathew, Dennis

    2016-01-01

    The ability of an animal to detect, discriminate, and respond to odors depends on the functions of its olfactory receptor neurons (ORNs). The extent to which each ORN, upon activation, contributes to chemotaxis is not well understood. We hypothesized that strong activation of each ORN elicits a different behavioral response in the Drosophila melanogaster larva by differentially affecting the composition of its navigational behavior. To test this hypothesis, we exposed Drosophila larvae to specific odorants to analyze the effect of individual ORN activity on chemotaxis. We used two different behavioral paradigms to analyze the chemotaxis response of larvae to odorants. When tested with five different odorants that elicit strong physiological responses from single ORNs, larval behavioral responses toward each odorant differed in the strength of attraction as well as in the composition of discrete navigational elements, such as runs and turns. Further, behavioral responses to odorants did not correlate with either the strength of odor gradients tested or the sensitivity of each ORN to its cognate odorant. Finally, we provide evidence that wild-type larvae with all ORNs intact exhibit higher behavioral variance than mutant larvae that have only a single pair of functional ORNs. We conclude that individual ORNs contribute differently to the olfactory circuit that instructs chemotactic responses. Our results, along with recent studies from other groups, suggest that ORNs are functionally nonequivalent units. These results have implications for understanding peripheral odor coding. PMID:27570823

  1. Interleukin-6 Receptor Polymorphisms Contribute to the Neurological Status of Korean Patients with Ischemic Stroke.

    PubMed

    Kim, Dong Hwan; Yoo, Seung Don; Chon, Jinmann; Yun, Dong Hwan; Kim, Hee-Sang; Park, Hae Jeong; Kim, Su Kang; Chung, Joo-Ho; Kang, Jin Kyu; Lee, Seung Ah

    2016-03-01

    To investigate the contribution of the interleukin-6 receptor (IL-6R) gene single nucleotide polymorphisms (SNPs) to the neurological status of Korean patients with ischemic stroke (IS), two SNPs of the IL-6R gene (rs4845617, 5 UTR; rs2228144, Ala31Ala) were selected. IS patients were classified into clinical phenotypes according to two well-defined scores: the National Institutes of Health Stroke Survey (NIHSS) and the Modified Barthel Index scores. There were 121 IS patients and 291 control subjects. The SNP rs4845617 significantly contributed to the neurological status of patients with IS (P = 0.011 in codominant model 2, P = 0.006 in recessive model, and P = 0.008 in log-additive model). Allele frequencies of rs4845617 and rs2228144 demonstrated no significant difference in IS patients and controls. The AG and GG haplotypes differed between the NIHSS 1 (NIHSS scores < 6) group and the NIHSS 2 (NIHSS scores ≥ 6) group in patients with IS (P = 0.014, P = 0.0024). These results suggest that rs4845617 of the IL-6R gene is associated with the neurologic status of Korean patients with IS. PMID:26955245

  2. S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke

    PubMed Central

    Shi, Zhong-Qing; Sunico, Carmen R.; McKercher, Scott R.; Cui, Jiankun; Feng, Gen-Sheng; Nakamura, Tomohiro; Lipton, Stuart A.

    2013-01-01

    Overproduction of nitric oxide (NO) can cause neuronal damage, contributing to the pathogenesis of several neurodegenerative diseases and stroke (i.e., focal cerebral ischemia). NO can mediate neurotoxic effects at least in part via protein S-nitrosylation, a reaction that covalently attaches NO to a cysteine thiol (or thiolate anion) to form an S-nitrosothiol. Recently, the tyrosine phosphatase Src homology region 2-containing protein tyrosine phosphatase-2 (SHP-2) and its downstream pathways have emerged as important mediators of cell survival. Here we report that in neurons and brain tissue NO can S-nitrosylate SHP-2 at its active site cysteine, forming S-nitrosylated SHP-2 (SNO–SHP-2). We found that NMDA exposure in vitro and transient focal cerebral ischemia in vivo resulted in increased levels of SNO–SHP-2. S-Nitrosylation of SHP-2 inhibited its phosphatase activity, blocking downstream activation of the neuroprotective physiological ERK1/2 pathway, thus increasing susceptibility to NMDA receptor-mediated excitotoxicity. These findings suggest that formation of SNO–SHP-2 represents a key chemical reaction contributing to excitotoxic damage in stroke and potentially other neurological disorders. PMID:23382182

  3. Interleukin-6 Receptor Polymorphisms Contribute to the Neurological Status of Korean Patients with Ischemic Stroke

    PubMed Central

    Yoo, Seung Don; Chon, Jinmann; Yun, Dong Hwan; Kim, Hee-Sang; Park, Hae Jeong; Kim, Su Kang; Chung, Joo-Ho; Kang, Jin Kyu

    2016-01-01

    To investigate the contribution of the interleukin-6 receptor (IL-6R) gene single nucleotide polymorphisms (SNPs) to the neurological status of Korean patients with ischemic stroke (IS), two SNPs of the IL-6R gene (rs4845617, 5 UTR; rs2228144, Ala31Ala) were selected. IS patients were classified into clinical phenotypes according to two well-defined scores: the National Institutes of Health Stroke Survey (NIHSS) and the Modified Barthel Index scores. There were 121 IS patients and 291 control subjects. The SNP rs4845617 significantly contributed to the neurological status of patients with IS (P = 0.011 in codominant model 2, P = 0.006 in recessive model, and P = 0.008 in log-additive model). Allele frequencies of rs4845617 and rs2228144 demonstrated no significant difference in IS patients and controls. The AG and GG haplotypes differed between the NIHSS 1 (NIHSS scores < 6) group and the NIHSS 2 (NIHSS scores ≥ 6) group in patients with IS (P = 0.014, P = 0.0024). These results suggest that rs4845617 of the IL-6R gene is associated with the neurologic status of Korean patients with IS. PMID:26955245

  4. Differential Contributions of Olfactory Receptor Neurons in a Drosophila Olfactory Circuit

    PubMed Central

    Newquist, Gunnar; Novenschi, Alexandra; Kohler, Donovan

    2016-01-01

    Abstract The ability of an animal to detect, discriminate, and respond to odors depends on the functions of its olfactory receptor neurons (ORNs). The extent to which each ORN, upon activation, contributes to chemotaxis is not well understood. We hypothesized that strong activation of each ORN elicits a different behavioral response in the Drosophila melanogaster larva by differentially affecting the composition of its navigational behavior. To test this hypothesis, we exposed Drosophila larvae to specific odorants to analyze the effect of individual ORN activity on chemotaxis. We used two different behavioral paradigms to analyze the chemotaxis response of larvae to odorants. When tested with five different odorants that elicit strong physiological responses from single ORNs, larval behavioral responses toward each odorant differed in the strength of attraction as well as in the composition of discrete navigational elements, such as runs and turns. Further, behavioral responses to odorants did not correlate with either the strength of odor gradients tested or the sensitivity of each ORN to its cognate odorant. Finally, we provide evidence that wild-type larvae with all ORNs intact exhibit higher behavioral variance than mutant larvae that have only a single pair of functional ORNs. We conclude that individual ORNs contribute differently to the olfactory circuit that instructs chemotactic responses. Our results, along with recent studies from other groups, suggest that ORNs are functionally nonequivalent units. These results have implications for understanding peripheral odor coding. PMID:27570823

  5. Developmental switch in the contribution of presynaptic and postsynaptic NMDA receptors to long-term depression.

    PubMed

    Corlew, Rebekah; Wang, Yun; Ghermazien, Haben; Erisir, Alev; Philpot, Benjamin D

    2007-09-12

    NMDA receptor (NMDAR) activation is required for many forms of learning and memory as well as sensory system receptive field plasticity, yet the relative contribution of presynaptic and postsynaptic NMDARs over cortical development remains unknown. Here we demonstrate a rapid developmental loss of functional presynaptic NMDARs in the neocortex. Presynaptic NMDARs enhance neurotransmitter release at synapses onto visual cortex pyramidal cells in young mice [before postnatal day 20 (P20)], but they have no apparent effect after the onset of the critical period for receptive field plasticity (>P23). Immunoelectron microscopy revealed that the loss of presynaptic NMDAR function is likely attributable in part to a 50% reduction in the prevalence of presynaptic NMDARs. Coincident with the observed loss of presynaptic NMDAR function, there is an abrupt change in the mechanisms of timing-dependent long-term depression (tLTD). Induction of tLTD before the onset of the critical period requires activation of presynaptic but not postsynaptic NMDARs, whereas the induction of tLTD in older mice requires activation of postsynaptic NMDARs. By demonstrating that both presynaptic and postsynaptic NMDARs contribute to the induction of synaptic plasticity and that their relative roles shift over development, our findings define a novel, and perhaps general, property of synaptic plasticity in emerging cortical circuits. PMID:17855598

  6. The contributions of oxytocin and vasopressin pathway genes to human behavior.

    PubMed

    Ebstein, Richard P; Knafo, Ariel; Mankuta, David; Chew, Soo Hong; Lai, Poh San

    2012-03-01

    Arginine vasopressin (AVP) and oxytocin (OXT) are social hormones and mediate affiliative behaviors in mammals and as recently demonstrated, also in humans. There is intense interest in how these simple nonapeptides mediate normal and abnormal behavior, especially regarding disorders of the social brain such as autism that are characterized by deficits in social communication and social skills. The current review examines in detail the behavioral genetics of the first level of human AVP-OXT pathway genes including arginine vasopressin 1a receptor (AVPR1a), oxytocin receptor (OXTR), AVP (AVP-neurophysin II [NPII]) and OXT (OXT neurophysin I [NPI]), oxytocinase/vasopressinase (LNPEP), ADP-ribosyl cyclase (CD38) and arginine vasopressin 1b receptor (AVPR1b). Wherever possible we discuss evidence from a variety of research tracks including molecular genetics, imaging genomics, pharmacology and endocrinology that support the conclusions drawn from association studies of social phenotypes and detail how common polymorphisms in AVP-OXT pathway genes contribute to the behavioral hard wiring that enables individual Homo sapiens to interact successfully with conspecifics. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior. PMID:22245314

  7. Bioassays for TSH Receptor Autoantibodies, from FRTL-5 Cells to TSH Receptor-LH/CG Receptor Chimeras: The Contribution of Leonard D. Kohn.

    PubMed

    Giuliani, Cesidio; Saji, Motoyasu; Bucci, Ines; Napolitano, Giorgio

    2016-01-01

    Since the discovery 60 years ago of the "long-acting thyroid stimulator" by Adams and Purves, great progress has been made in the detection of thyroid-stimulating hormone (TSH) receptor (TSHR) autoantibodies (TRAbs) in Graves' disease. Today, commercial assays are available that can detect TRAbs with high accuracy and provide diagnostic and prognostic evaluation of patients with Graves' disease. The present review focuses on the development of TRAbs bioassays, and particularly on the role that Leonard D. Kohn had in this. Indeed, 30 years ago, the Kohn group developed a bioassay based on the use of FRTL-5 cells that was characterized by high reproducibility, feasibility, and diagnostic accuracy. Using this FRTL-5 bioassay, Kohn and his colleagues were the first to develop monoclonal antibodies (moAbs) against the TSHR. Furthermore, they demonstrated the multifaceted functional nature of TRAbs in patients with Graves' disease, with the identification of stimulating and blocking TRAbs, and even antibodies that activated pathways other than cAMP. After the cloning of the TSHR, the Kohn laboratory constructed human TSHR-rat luteinizing hormone/chorionic gonadotropin receptor chimeras. This paved the way to a new bioassay based on the use of non-thyroid cells transfected with the Mc4 chimera. The new Mc4 bioassay is characterized by high diagnostic and prognostic accuracy, greater than for other assays. The availability of a commercial kit based on the Mc4 chimera is spreading the use of this assay worldwide, indicating its benefits for these patients with Graves' disease. This review also describes the main contributions made by other researchers in TSHR molecular biology and TRAbs assay, especially with the development of highly potent moAbs. A comparison of the diagnostic accuracies of the main TRAbs assays, as both immunoassays and bioassays, is also provided. PMID:27504107

  8. The atypical chemokine receptor D6 contributes to the development of experimental colitis1

    PubMed Central

    Bordon, Yvonne; Hansell, Chris A. H.; Sester, David P; Clarke, Mairi; Mowat, Allan McI.; Nibbs, Robert J. B.

    2009-01-01

    Pro-inflammatory CC chemokines control leukocyte recruitment and function during inflammation by engaging chemokine receptors expressed on circulating leukocytes. The D6 chemokine receptor can bind several of these chemokines but appears unable to couple to signal transduction pathways or direct cell migration. Instead, D6 has been proposed to act as a chemokine scavenger, removing pro-inflammatory chemokines to dampen leukocyte responses. In this report, we have examined the role of D6 in the colon using the dextran sodium sulphate-induced model of colitis. We show that D6 is expressed in the resting colon, predominantly by stromal cells and B cells, and is up-regulated during colitis. Unexpectedly, D6-deficient mice showed reduced susceptibility to colitis and had less pronounced clinical symptoms associated with this model. D6 deletion had no impact on the level of pro-inflammatory CC chemokines released from cultured colon explants, or on the balance of leukocyte subsets recruited to the inflamed colon. However, late in colitis, inflamed D6-deficient colons showed enhanced production of several pro-inflammatory cytokines, including IFNγ and IL-17A, and there was a marked increase in IL-17A-secreting γδ T cells in the lamina propria. Moreover, antibody-mediated neutralisation of IL-17A worsened the clinical symptoms of colitis at these later stages of the response in D6-deficient, but not wild-type, mice. Thus, D6 can contribute to the development of colitis by regulating IL-17A secretion by γδ T cells in the inflamed colon. PMID:19342683

  9. Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis.

    PubMed

    Di Giacomo, Daniele; De Domenico, Emanuela; Sette, Claudio; Geremia, Raffaele; Grimaldi, Paola

    2016-04-01

    Type 2 cannabinoid receptor (CB2) has been proposed to play a pivotal role in meiotic entry of male germ cells, similar to retinoic acid (RA). In this study, we showed that activation of CB2with the specific agonist JWH133 [3-(1',1'-dimethylbutyl)-1-deoxy-8-THC] (IC5010(-6)M) mimics epigenetic events induced by RA (IC5010(-7)M) in spermatogonia. Both JWH133 and RA treatments stimulate the expression of the meiotic genes c-KitandStra8, by up-regulating H3K4me3 and down-regulating H3K9me2 levels in genomic regions flanking the transcription start site. Moreover, both agents increase the expression ofPrdm9, the gene encoding a meiosis-specific histone, H3K4me3 methyltransferase, which marks hotspots of recombination in prophase I, thus resulting in a global increase in H3K4me3. Notably, prolonged administration of JWH133 to immature 7 dpp CD-1 mice induced an acceleration of the onset of spermatogenesis, whereas the specific CB2antagonist delayed germ cell differentiation. Thus, both hyper- and hypostimulation of CB2disrupted the temporal dynamics of the spermatogenic cycle. These findings highlight the importance of proper CB2signaling for the maintenance of a correct temporal progression of spermatogenesis and suggest a possible adverse effect of cannabis in deregulating this process.-Di Giacomo, D., De Domenico, E., Sette, C., Geremia, R., Grimaldi, P. Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis. PMID:26671998

  10. SCAVENGER RECEPTORS FOUND ON CHICKEN HETEROPHILS CONTRIBUTE TO THE PHAGOCYTOSIS OF SALMONELLA ENTERITIDIS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pattern recognition receptors (PRR) are a critical component of the innate immune response and the hosts¿ ability to recognize self from infectious non-self. Scavenger receptors (SR), a type of PRR, are cell surface glycoproteins involved in receptor-mediated phagocytosis of polyanionic ligands. H...

  11. A multivariate receptor modeling study of air-borne particulate PAHs: Regional contributions in a roadside environment.

    PubMed

    Kim, Bong Mann; Lee, Seung-Bok; Kim, Jin Young; Kim, Sunwha; Seo, Jihoon; Bae, Gwi-Nam; Lee, Ji Yi

    2016-02-01

    Understanding the geographic source contributions by particulate polycyclic aromatic hydrocarbons (PAHs) is important for the Korean peninsula due to its downwind location from source areas. Regional influence of particulate PAHs was previously identified using diagnostic ratios applied to mobile source dominated roadside sampling data (Kim et al., 2012b). However, no study has yet been conducted to quantify the regional source contributions. We applied a multivariate receptor modeling tool to identify and quantify the regional source contributions to particulate PAHs in Seoul. Sampling of roadside particulate PAHs was conducted in Seoul, Korea for four years between May 2005 and April 2009, and data analysis was performed with a new multivariate receptor model, Solver for Mixture Problem (SMP). The SMP model identified two sources, local mobile source and transported regional source, and quantified their source contributions. Analysis of the particulate PAHs data reveals three types of episodic periods: a high regional source contribution period with one case, a high mobile source contribution period with three cases, and a normal contribution period with eight cases. Four-year average particulate PAHs source contributions from the two sources are 4.6 ng m(-3) and 10.7 ng m(-3) for regional and mobile sources, respectively and equivalent to 30% and 70% of the total estimated contribution from each of these sources. PMID:26473551

  12. Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia

    PubMed Central

    Swick, Jennifer C; Alhadeff, Amber L; Grill, Harvey J; Urrea, Paula; Lee, Stephanie M; Roh, Hyunsun; Baird, John-Paul

    2015-01-01

    Exendin-4 (Ex4), a glucagon-like peptide-1 receptor (GLP-1R) agonist approved to treat type 2 diabetes mellitus, is well known to induce hypophagia in human and animal models. We evaluated the contributions of the hindbrain parabrachial nucleus (PBN) to systemic Ex4-induced hypophagia, as the PBN receives gustatory and visceral afferent relays and descending input from several brain nuclei associated with feeding. Rats with ibotenic-acid lesions targeted to the lateral PBN (PBNx) and sham controls received Ex4 (1 μg/kg) before 24 h home cage chow or 90 min 0.3 M sucrose access tests, and licking microstructure was analyzed to identify components of feeding behavior affected by Ex4. PBN lesion efficacy was confirmed using conditioned taste aversion (CTA) tests. As expected, sham control but not PBNx rats developed a CTA. In sham-lesioned rats, Ex4 reduced chow intake within 4 h of injection and sucrose intake within 90 min. PBNx rats did not show reduced chow or sucrose intake after Ex4 treatment, indicating that the PBN is necessary for Ex4 effects under the conditions tested. In sham-treated rats, Ex4 affected licking microstructure measures associated with hedonic taste evaluation, appetitive behavior, oromotor coordination, and inhibitory postingestive feedback. Licking microstructure responses in PBNx rats after Ex4 treatment were similar to sham-treated rats with the exception of inhibitory postingestive feedback measures. Together, the results suggest that the PBN critically contributes to the hypophagic effects of systemically delivered GLP-1R agonists by enhancing visceral feedback. PMID:25703200

  13. Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia.

    PubMed

    Swick, Jennifer C; Alhadeff, Amber L; Grill, Harvey J; Urrea, Paula; Lee, Stephanie M; Roh, Hyunsun; Baird, John-Paul

    2015-07-01

    Exendin-4 (Ex4), a glucagon-like peptide-1 receptor (GLP-1R) agonist approved to treat type 2 diabetes mellitus, is well known to induce hypophagia in human and animal models. We evaluated the contributions of the hindbrain parabrachial nucleus (PBN) to systemic Ex4-induced hypophagia, as the PBN receives gustatory and visceral afferent relays and descending input from several brain nuclei associated with feeding. Rats with ibotenic-acid lesions targeted to the lateral PBN (PBNx) and sham controls received Ex4 (1 μg/kg) before 24 h home cage chow or 90 min 0.3 M sucrose access tests, and licking microstructure was analyzed to identify components of feeding behavior affected by Ex4. PBN lesion efficacy was confirmed using conditioned taste aversion (CTA) tests. As expected, sham control but not PBNx rats developed a CTA. In sham-lesioned rats, Ex4 reduced chow intake within 4 h of injection and sucrose intake within 90 min. PBNx rats did not show reduced chow or sucrose intake after Ex4 treatment, indicating that the PBN is necessary for Ex4 effects under the conditions tested. In sham-treated rats, Ex4 affected licking microstructure measures associated with hedonic taste evaluation, appetitive behavior, oromotor coordination, and inhibitory postingestive feedback. Licking microstructure responses in PBNx rats after Ex4 treatment were similar to sham-treated rats with the exception of inhibitory postingestive feedback measures. Together, the results suggest that the PBN critically contributes to the hypophagic effects of systemically delivered GLP-1R agonists by enhancing visceral feedback. PMID:25703200

  14. Functional Phylogenetics Reveals Contributions of Pleiotropic Peptide Action to Ligand-Receptor Coevolution

    PubMed Central

    Jiang, Hongbo; Wei, Zhaojun; Nachman, Ronald J.; Adams, Michael E.; Park, Yoonseong

    2014-01-01

    The evolution of peptidergic signaling has been accompanied by a significant degree of ligand-receptor coevolution. Closely related clusters of peptide signaling molecules are observed to activate related groups of receptors, implying that genes encoding these ligands may orchestrate an array of functions, a phenomenon known as pleiotropy. Here we examine whether pleiotropic actions of peptide genes might influence ligand-receptor coevolution. Four test groups of neuropeptides characterized by conserved C-terminal amino acid sequence motifs and their cognate receptors were examined in the red flour beetle (Tribolium castaneum): 1) cardioacceleratory peptide 2b (CAPA); CAPAr, 2) pyrokinin/diapause hormone (PK1/DH); PKr-A, -B, 3) pyrokinin/pheromone biosynthesis activating hormone (PK2/PBAN); PKr-C, and 4) ecdysis triggering hormone (ETH); ETHr-b. Ligand-receptor specificities were established through heterologous expression of receptors in cell-based assays for 9 endogenous ligands. Based on ligand-receptor specificity analysis, we found positive pleiotropism exhibited by ETH on ETHR-b and CAPAr, whereas PK1/DH and CAPA are more highly selective for their respective authentic receptors than would be predicted by phylogenetic analysis. Disparities between evolutionary trees deduced from receptor sequences vs. functional ligand-receptor specificities lead to the conclusion that pleiotropy exhibited by peptide genes influences ligand-receptor coevolution. PMID:25348027

  15. Transient Receptor Potential Vanilloid-1 in Epidermal Keratinocytes May Contribute to Acute Pain in Herpes Zoster.

    PubMed

    Han, Sang Bum; Kim, Hyeree; Cho, Sang Hyun; Lee, Jeong Deuk; Chung, Jin Ho; Kim, Hei Sung

    2016-03-01

    The role of transient receptor potential vanilloid-1 (TRPV1) in the initiation of neurogenic inflammation and transduction of pain is well established. In this study 33 patients with herpes zoster (HZ) were recruited from a single centre and underwent a questionnaire interview at their first visit. Punch biopsies from the HZ lesions and the contralateral unaffected skin were performed to localize and quantify the expression of TRPV1. Immunofluorescent staining for TRPV1 was most prominent in the epidermal keratinocytes. Both TRPV1 mRNA and protein levels were significantly higher in the HZ epidermis than in control epidermis (relative ratio 1.62 ± 0.27, p = 0.033 and 2.55 ± 0.51, p = 0.005, respectively). Protein TRPV1 ratio (HZ lesion/control) correlated with the degree of pain (measured on a visual analogue scale; VAS) (p = 0.017) and was significantly lower in patients who had taken either HZ medication or painkillers prior to their visit. These results suggest that non-neuronal TRPV1 may contribute to acute pain in herpes zoster. PMID:26390894

  16. Contribution of the receptor guanylyl cyclase GC-D to chemosensory function in the olfactory epithelium

    PubMed Central

    Leinders-Zufall, Trese; Cockerham, Renee E.; Michalakis, Stylianos; Biel, Martin; Garbers, David L.; Reed, Randall R.; Zufall, Frank; Munger, Steven D.

    2007-01-01

    The mammalian main olfactory epithelium (MOE) recognizes and transduces olfactory cues through a G protein-coupled, cAMP-dependent signaling cascade. Additional chemosensory transduction mechanisms have been suggested but remain controversial. We show that a subset of MOE neurons expressing the orphan receptor guanylyl cyclase GC-D and the cyclic nucleotide-gated channel subunit CNGA3 employ an excitatory cGMP-dependent transduction mechanism for chemodetection. By combining gene targeting of Gucy2d, which encodes GC-D, with patch clamp recording and confocal Ca2+ imaging from single dendritic knobs in situ, we find that GC-D cells recognize the peptide hormones uroguanylin and guanylin as well as natural urine stimuli. These molecules stimulate an excitatory, cGMP-dependent signaling cascade that increases intracellular Ca2+ and action potential firing. Responses are eliminated in both Gucy2d- and Cnga3-null mice, demonstrating the essential role of GC-D and CNGA3 in the transduction of these molecules. The sensitive and selective detection of two important natriuretic peptides by the GC-D neurons suggests the possibility that these cells contribute to the maintenance of salt and water homeostasis or the detection of cues related to hunger, satiety, or thirst. PMID:17724338

  17. Upregulation of Transient Receptor Potential Canonical Channels Contributes to Endotoxin-Induced Pulmonary Arterial Stenosis

    PubMed Central

    Chen, Gui-Lan; Jiang, Hongni; Zou, Fangdong

    2016-01-01

    Background Septic shock is a pathologic condition caused by endotoxin-producing bacteria, and often associated with severe pulmonary hypertension. Inflammation is a major systemic response to endotoxin; however, it is unknown whether endotoxin has a direct impact on pulmonary arteries that contributes to pathogenesis of pulmonary hypertension. Material/Methods Rat pulmonary arteries and primary pulmonary arterial smooth muscle cells (PASMCs) were cultured in vitro and treated with lipopolysaccharide (LPS) and blockers of transient receptor potential canonical (TRPC) channels. Neointimal growth and arterial stenosis were observed on cryosections of cultured pulmonary arteries. Proliferation of PASMCs was examined by a WST-1 (water-soluble tetrazolium salt) assay. Expression of TRPC genes in pulmonary arteries and PASMCs were detected and quantified by real-time polymerase chain reaction and Western blotting. Results LPS significantly induced neointimal growth and stenosis of pulmonary arteries and promoted proliferation of PASMCs. TRPC channel blockers 2-aminoethoxydiphenyl borate and SKF-96365 inhibited LPS-induced remodeling of pulmonary arteries and PASMC proliferation. Expression of TRPC1/3/4/6 was detected in pulmonary arteries and PASMCs. LPS treatment dramatically increased the expression of TRPC3 and TRPC4 at both messenger RNA and protein levels. Conclusions LPS stimulates stenosis of pulmonary arteries through enhancement of TRPC-mediated Ca2+ entry into PASMCs, which is caused by upregulation of TRPC3 and TRPC4 channels. PMID:27471122

  18. Transient receptor potential melastatin 4 channel contributes to migration of androgen-insensitive prostate cancer cells

    PubMed Central

    Kilch, Tatiana; Jochum, Marcus Martin; Urban, Sabine Katharina; Jung, Volker; Stöckle, Michael; Rother, Karen; Greiner, Markus; Peinelt, Christine

    2015-01-01

    Impaired Ca2+ signaling in prostate cancer contributes to several cancer hallmarks, such as enhanced proliferation and migration and a decreased ability to induce apoptosis. Na+ influx via transient receptor potential melastatin 4 channel (TRPM4) can reduce store-operated Ca2+ entry (SOCE) by decreasing the driving force for Ca2+. In patients with prostate cancer, gene expression of TRPM4 is elevated. Recently, TRPM4 was identified as a cancer driver gene in androgen-insensitive prostate cancer. We investigated TRPM4 protein expression in cancer tissue samples from 20 patients with prostate cancer. We found elevated TRPM4 protein levels in prostatic intraepithelial neoplasia (PIN) and prostate cancer tissue compared to healthy tissue. In primary human prostate epithelial cells (hPEC) from healthy tissue and in the androgen-insensitive prostate cancer cell lines DU145 and PC3, TRPM4 mediated large Na+ currents. We demonstrated significantly increased SOCE after siRNA targeting of TRPM4 in hPEC and DU145 cells. In addition, knockdown of TRPM4 reduced migration but not proliferation of DU145 and PC3 cells. Taken together, our data identify TRPM4 as a regulator of SOCE in hPEC and DU145 cells, demonstrate a role for TRPM4 in cancer cell migration and suggest that TRPM4 is a promising potential therapeutic target. PMID:26496025

  19. The Soluble VEGF Receptor sFlt1 Contributes to Endothelial Dysfunction in CKD

    PubMed Central

    Marco, Giovana S. Di; Reuter, Stefan; Hillebrand, Uta; Amler, Susanne; König, Maximilian; Larger, Etienne; Oberleithner, Hans; Brand, Eva; Pavenstädt, Hermann

    2009-01-01

    Endothelial dysfunction contributes to the increased cardiovascular risk that accompanies CKD. We hypothesized that the soluble VEGF receptor 1 (sFlt-1), a VEGF antagonist, plays a role in endothelial dysfunction and decreased angiogenesis in CKD. We enrolled 130 patients with CKD stages 3 to 5 and 56 age- and gender-matched control patients. Plasma sFlt-1 levels were higher in patients with CKD and, after multivariate regression analyses, exclusively associated with renal function and levels of vWF, a marker of endothelial dysfunction. Compared with serum from control patients, both recombinant sFlt-1 and serum from patients with CKD had antiangiogenic activity in the chick chorioallantoic membrane (CAM) assay, induced endothelial cell apoptosis in vitro, and decreased nitric oxide generation in two different endothelial cell lines. Pretreating the sera with an antibody against sFlt-1 abrogated all of these effects. Furthermore, we observed increased sFlt1 levels in 5/6-nephrectomized rats compared with sham-operated animals. Finally, using real-time PCR and ELISA, we identified monocytes as a possible source of increased sFlt-1 in patients with CKD. Our findings show that excess sFlt-1 associates with endothelial dysfunction in CKD and suggest that increased sFlt-1 may predict cardiovascular risk in CKD. PMID:19608702

  20. [Contributions of neuropsychology to anti-NMDA receptor antibody encephalitis: a literature review].

    PubMed

    Luna-Lario, P; Hernaez-Goni, P; Tirapu-Ustarroz, J

    2016-05-01

    Limbic encephalitis generated by anti-N-methyl-D-aspartate (NMDA) receptor antibodies is an acute and severe neurological entity, which is more prevalent in young females and is associated to an underlying tumour. Since it leads to severe cognitive impairment, thought needs to be given to the contributions of neuropsychology to the diagnosis, development and treatment of the disease, which have received little attention from researchers to date. A review is conducted of the prior literature, evaluating the measurement of the cognitive symptoms (predominantly mnemonic and executive) associated to this disease. Valid, reliable neuropsychological instruments are proposed, and it is suggested that neuropsychological measures may be used as parameters to follow up these patients which help monitor their functionality in daily living once they have recovered from the acute phase. Similarly they can become a basis on which to assemble rehabilitation programmes that favour the accomplishment of personal autonomy and the patients' reintegration in the community. Nevertheless, we stress the need to include neuropsychologists and neuropsychiatrists in not only the detection but also the treatment of these patients so as to enable them to recover their personal independence and re-adapt to their natural settings. PMID:27113067

  1. Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain.

    PubMed

    Borg, J; Cervenka, S; Kuja-Halkola, R; Matheson, G J; Jönsson, E G; Lichtenstein, P; Henningsson, S; Ichimiya, T; Larsson, H; Stenkrona, P; Halldin, C; Farde, L

    2016-08-01

    The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [(11)C]raclopride binding to the D2- and D3-dopamine receptor and [(11)C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70-0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature-nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease. PMID:26821979

  2. Multiple compound-related adverse properties contribute to liver injury caused by endothelin receptor antagonists.

    PubMed

    Kenna, J Gerry; Stahl, Simone H; Eakins, Julie A; Foster, Alison J; Andersson, Linda C; Bergare, Jonas; Billger, Martin; Elebring, Marie; Elmore, Charles S; Thompson, Richard A

    2015-02-01

    Drug-induced liver injury has been observed in patients treated with the endothelin receptor antagonists sitaxentan and bosentan, but not following treatment with ambrisentan. The aim of our studies was to assess the possible role of multiple contributory mechanisms in this clinically relevant toxicity. Inhibition of the bile salt export pump (BSEP) and multidrug resistance-associated protein 2 was quantified using membrane vesicle assays. Inhibition of mitochondrial respiration in human liver-derived HuH-7 cells was determined using a Seahorse XF(e96) analyzer. Cytochrome P450 (P450)-independent and P450-mediated cell toxicity was assessed using transfected SV40-T-antigen-immortalized human liver epithelial (THLE) cell lines. Exposure-adjusted assay ratios were calculated by dividing the maximum human drug plasma concentrations by the IC50 or EC50 values obtained in vitro. Covalent binding (CVB) of radiolabeled drugs to human hepatocytes was quantified, and CVB body burdens were calculated by adjusting CVB values for fractional drug turnover in vitro and daily therapeutic dose. Sitaxentan exhibited positive exposure-adjusted signals in all five in vitro assays and a high CVB body burden. Bosentan exhibited a positive exposure-adjusted signal in one assay (BSEP inhibition) and a moderate CVB body burden. Ambrisentan exhibited no positive exposure-adjusted assay signals and a low CVB body burden. These data indicate that multiple mechanisms contribute to the rare, but potentially severe liver injury caused by sitaxentan in humans; provide a plausible rationale for the markedly lower propensity of bosentan to cause liver injury; and highlight the relative safety of ambrisentan. PMID:25467130

  3. Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors

    PubMed Central

    Yuan, Amy; Lee, Yashang; Choi, Uimook; Moeckel, Gilbert

    2014-01-01

    Kidney fibrosis is the final common pathway for virtually every type of chronic kidney disease and is a consequence of a prolonged healing response that follows tissue inflammation. Chronic kidney inflammation ultimately leads to progressive tissue injury and scarring/fibrosis. Several pathways have been implicated in the progression of kidney fibrosis. In the present study, we demonstrate that G protein-coupled chemokine (C-X-C motif) receptor (CXCR)4 was significantly upregulated after renal injury and that sustained activation of Cxcr4 expression augmented the fibrotic response. We demonstrate that after unilateral ureteral obstruction (UUO), both gene and protein expression of Cxcr4 were highly upregulated in tubular cells of the nephron. The increased Cxcr4 expression in tubules correlated with their increased dedifferentiated state, leading to increased mRNA expression of platelet-derived growth factor (PDGF)-α, transforming growth factor (TGF)-β1, and concurrent loss of bone morphogenetic protein 7 (Bmp7). Ablation of tubular Cxcr4 attenuated UUO-mediated fibrotic responses, which correlated with a significant reduction in PDGF-α and TGF-β1 levels and preservation of Bmp7 expression after UUO. Furthermore, Cxcr4+ immune cells infiltrated the obstructed kidney and further upregulate their Cxcr4 expression. Genetic ablation of Cxcr4 from macrophages was protective against UUO-induced fibrosis. There was also reduced total kidney TGF-β1, which correlated with reduced Smad activation and α-smooth muscle actin levels. We conclude that chronic high Cxcr4 expression in multiple effector cell types can contribute to the pathogenesis of renal fibrosis by altering their biological profile. This study uncovered a novel cross-talk between Cxcr4-TGF-β1 and Bmp7 pathways and may provide novel targets for interrupting the progression of fibrosis. PMID:25537742

  4. Chemokine receptor Cxcr4 contributes to kidney fibrosis via multiple effectors.

    PubMed

    Yuan, Amy; Lee, Yashang; Choi, Uimook; Moeckel, Gilbert; Karihaloo, Anil

    2015-03-01

    Kidney fibrosis is the final common pathway for virtually every type of chronic kidney disease and is a consequence of a prolonged healing response that follows tissue inflammation. Chronic kidney inflammation ultimately leads to progressive tissue injury and scarring/fibrosis. Several pathways have been implicated in the progression of kidney fibrosis. In the present study, we demonstrate that G protein-coupled chemokine (C-X-C motif) receptor (CXCR)4 was significantly upregulated after renal injury and that sustained activation of Cxcr4 expression augmented the fibrotic response. We demonstrate that after unilateral ureteral obstruction (UUO), both gene and protein expression of Cxcr4 were highly upregulated in tubular cells of the nephron. The increased Cxcr4 expression in tubules correlated with their increased dedifferentiated state, leading to increased mRNA expression of platelet-derived growth factor (PDGF)-α, transforming growth factor (TGF)-β1, and concurrent loss of bone morphogenetic protein 7 (Bmp7). Ablation of tubular Cxcr4 attenuated UUO-mediated fibrotic responses, which correlated with a significant reduction in PDGF-α and TGF-β1 levels and preservation of Bmp7 expression after UUO. Furthermore, Cxcr4(+) immune cells infiltrated the obstructed kidney and further upregulate their Cxcr4 expression. Genetic ablation of Cxcr4 from macrophages was protective against UUO-induced fibrosis. There was also reduced total kidney TGF-β1, which correlated with reduced Smad activation and α-smooth muscle actin levels. We conclude that chronic high Cxcr4 expression in multiple effector cell types can contribute to the pathogenesis of renal fibrosis by altering their biological profile. This study uncovered a novel cross-talk between Cxcr4-TGF-β1 and Bmp7 pathways and may provide novel targets for interrupting the progression of fibrosis. PMID:25537742

  5. Expression of Toll-Like Receptor 4 Contributes to Corneal Inflammation in Experimental Dry Eye Disease

    PubMed Central

    Lee, Hyun Soo; Hattori, Takaaki; Park, Eun Young; Stevenson, William; Chauhan, Sunil K.; Dana, Reza

    2012-01-01

    Purpose. To investigate the corneal expression of toll-like receptor (TLR) 4 and determine its contribution to the immunopathogenesis of dry eye disease (DED). Methods. Seven to 8-week-old female C57BL/6 mice were housed in a controlled environment chamber and administered scopolamine to induce experimental DED. Mice received intravenous TLR4 inhibitor (Eritoran) to block systemic TLR4-mediated activity. The expression of TLR4 by the corneal epithelium and stroma was evaluated using real-time polymerase chain reaction and flow cytometry. Corneal fluorescein staining (CFS) was performed to evaluate clinical disease severity. The corneal expression of proinflammatory cytokines (IL-1β, IL-6, TNF, and CCL2), corneal infiltration of CD11b+ antigen-presenting cells, and lymph node frequency of mature MHC-IIhi CD11b+ cells were assessed. Results. The epithelial cells of normal corneas expressed TLR4 intracellularly; however, DED significantly increased the cell surface expression of TLR4. Similarly, flow cytometric analysis of stromal cells revealed a significant increase in the expression of TLR4 proteins by DED-induced corneas as compared with normal corneas. DED increased the mRNA expression of TLR4 in corneal stromal cells, but not epithelial cells. TLR4 inhibition decreased the severity of CFS and significantly reduced the mRNA expression of IL-1β, IL-6, and TNF. Furthermore, TLR4 inhibition significantly reduced the corneal infiltration of CD11b+ cells and the lymph node frequency of MHC-IIhi CD11b+ cells. Conclusions. These results suggest that DED increases the corneal expression of TLR4 and that TLR4 participates in the inflammatory response to ocular surface desiccating stress. PMID:22789921

  6. Functional phylogenetics reveals contributions of pleiotropic peptide action to ligand-receptor coevolution

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The evolution of peptidergic signaling has been accompanied by a significant degree of ligand-receptor coevolution. Closely related clusters of peptide signaling molecules are observed to activate related groups of receptors, implying that genes encoding these ligands may orchestrate an array of fu...

  7. Kinetic contributions to gating by interactions unique to N-methyl-D-aspartate (NMDA) receptors.

    PubMed

    Borschel, William F; Cummings, Kirstie A; Tindell, LeeAnn K; Popescu, Gabriela K

    2015-10-30

    Among glutamate-gated channels, NMDA receptors produce currents that subside with unusually slow kinetics, and this feature is essential to the physiology of central excitatory synapses. Relative to the homologous AMPA and kainate receptors, NMDA receptors have additional intersubunit contacts in the ligand binding domain that occur at both conserved and non-conserved sites. We examined GluN1/GluN2A single-channel currents with kinetic analyses and modeling to probe these class-specific intersubunit interactions for their role in glutamate binding and receptor gating. We found that substitutions that eliminate such interactions at non-conserved sites reduced stationary gating, accelerated deactivation, and imparted sensitivity to aniracetam, an AMPA receptor-selective positive modulator. Abolishing unique contacts at conserved sites also reduced stationary gating and accelerated deactivation. These results show that contacts specific to NMDA receptors, which brace the heterodimer interface within the ligand binding domain, stabilize actively gating receptor conformations and result in longer bursts and slower deactivations. They support the view that the strength of the heterodimer interface modulates gating in both NMDA and non-NMDA receptors and that unique interactions at this interface are responsible in part for basic differences between the kinetics of NMDA and non-NMDA currents at glutamatergic synapses. PMID:26370091

  8. α₁-Adrenergic receptors contribute to the acute effects of 3,4-methylenedioxymethamphetamine in humans.

    PubMed

    Hysek, Cédric M; Fink, Anja E; Simmler, Linda D; Donzelli, Massimiliano; Grouzmann, Eric; Liechti, Matthias E

    2013-10-01

    Preclinical studies implicate a role for α₁-noradrenergic receptors in the effects of psychostimulants, including 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). The present study evaluated the effects of the α₁-noradrenergic receptor antagonist doxazosin on the acute pharmacodynamic and pharmacokinetic response to MDMA in 16 healthy subjects. Doxazosin (8 mg/d) or placebo was administered for 3 days before MDMA (125 mg) or placebo using a randomized, double-blind, placebo-controlled, 4-session, crossover design. Doxazosin reduced MDMA-induced elevations in blood pressure, body temperature, and moderately attenuated positive mood but enhanced tachycardia associated with MDMA. The results indicate that α₁-adrenergic receptors contribute to the acute cardiostimulant and to a minor extent possibly also to the thermogenic and euphoric effects of MDMA in humans. PMID:23857311

  9. Contributions of conserved serine residues to the interactions of ligands with dopamine D2 receptors.

    PubMed

    Cox, B A; Henningsen, R A; Spanoyannis, A; Neve, R L; Neve, K A

    1992-08-01

    Four dopamine D2 receptor mutants were constructed, in each of which an alanine residue was substituted for one of four conserved serine residues, i.e., Ser-193, Ser-194, Ser-197, and Ser-391. Wild-type and mutant receptors were expressed transiently in COS-7 cells and stably in C6 glioma cells for analysis of ligand-receptor interactions. In radioligand binding assays, the affinity of D2 receptors for dopamine was decreased 50-fold by substitution of alanine for Ser-193, implicating this residue in the binding of dopamine. Each mutant had smaller decreases in affinity for one or more of the ligands tested, with no apparent relationship between the class of ligand and the pattern of mutation-induced changes in affinity, except that the potency of agonists was decreased by substitution for Ser-193. The potency of dopamine for inhibition of adenylyl cyclase was reduced substantially by substitution of alanine for Ser-193 or Ser-197. Mutation of Ser-194 led to a complete loss of efficacy for dopamine and p-tyramine, which would be consistent with an interaction between Ser-194 and the p-hydroxyl substituent of dopamine that is necessary for activation of the receptors to occur. Because mutation of the corresponding residues of beta 2-adrenergic receptors has very different consequences, we conclude that although the position of these serine residues is highly conserved among catecholamine receptors, and the residues as a group are important in ligand binding and activation of receptors by agonists, the function of each of the residues considered separately varies among catecholamine receptors. PMID:1321233

  10. Evaluation of the Contribution of Multiple DAMPs and DAMP Receptors in Cell Death-Induced Sterile Inflammatory Responses

    PubMed Central

    Patel, Zubin; Rock, Kenneth L.

    2014-01-01

    When cells die by necrosis in vivo they stimulate an inflammatory response. It is thought that this response is triggered when the injured cells expose proinflammatory molecules, collectively referred to as damage associated molecular patterns (DAMPs), which are recognized by cells or soluble molecules of the innate or adaptive immune system. Several putative DAMPs and/or their receptors have been identified, but whether and how much they participate in responses in vivo is incompletely understood, and they have not previously been compared side-by-side in the same models. This study focuses on evaluating the contribution of multiple mechanisms that have been proposed to or potentially could participate in cell death-induced inflammation: The third component of complement (C3), ATP (and its receptor P2X7), antibodies, the C-type lectin receptor Mincle (Clec4e), and protease-activated receptor 2 (PAR2). We investigate the role of these factors in cell death-induced inflammation to dead cells in the peritoneum and acetaminophen-induced liver damage. We find that mice deficient in antibody, C3 or PAR2 have impaired inflammatory responses to dying cells. In contrast there was no reduction in inflammation to cell death in the peritoneum or liver of mice that genetically lack Mincle, the P2X7 receptor or that were treated with apyrase to deplete ATP. These results indicate that antibody, complement and PAR2 contribute to cell death-induced inflammation but that Mincle and ATP- P2X7 receptor are not required for this response in at least 2 different in vivo models. PMID:25127469

  11. NMDA Receptor Agonism and Antagonism within the Amygdaloid Central Nucleus Suppresses Pain Affect: Differential Contribution of the Ventrolateral Periaqueductal Gray

    PubMed Central

    Spuz, Catherine A.; Tomaszycki, Michelle L.; Borszcz, George S.

    2015-01-01

    The amygdala contributes to the generation of pain affect and the amygdaloid central nucleus (CeA) receives nociceptive input that is mediated by glutamatergic neurotransmission. The present study compared the contribution of N-methyl-D-aspartate (NMDA) receptor agonism and antagonism in CeA to generation of the affective response of rats to an acute noxious stimulus. Vocalizations that occur following a brief tail shock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed, in a dose dependent manner, by bilateral injection into CeA of NMDA (.1 µg, .25 µg, .5 µg, or 1 µg/side), or the NMDA receptor antagonist D-2-amino-5-phosphonovalerate (AP5, 1 µg, 2 µg, or 4 µg/side). Vocalizations that occur during tail shock were suppressed to a lesser degree, whereas, spinal motor reflexes (tail flick and hind limb movements) were unaffected by injection of NMDA or AP5 into CeA. Injection of NMDA, but not AP5, into CeA increased c-Fos immunoreactivity in the ventrolateral periaqueductal gray (vlPAG), and unilateral injection of the µ-opiate receptor antagonist H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP, 0.25 µg) into vlPAG prevented the antinociception generated by injection of NMDA into CeA. These findings demonstrate that although NMDA receptor agonism and antagonism in CeA produce similar suppression of pain behaviors they do so via different neurobiological mechanisms. Perspective The amygdala contributes to production of the emotional dimension of pain. NMDA receptor agonism and antagonism within the central nucleus of the amygdala suppressed rats’ emotional response to acute painful stimulation. Understanding the neurobiology underlying emotional responses to pain will provide insights into new treatments for pain and its associated affective disorders. PMID:25261341

  12. Potentiation of the transient receptor potential vanilloid 1 channel contributes to pruritogenesis in a rat model of liver disease.

    PubMed

    Belghiti, Majedeline; Estévez-Herrera, Judith; Giménez-Garzó, Carla; González-Usano, Alba; Montoliu, Carmina; Ferrer-Montiel, Antonio; Felipo, Vicente; Planells-Cases, Rosa

    2013-04-01

    Persistent pruritus is a common disabling dermatologic symptom associated with different etiologic factors. These include primary skin conditions, as well as neuropathic, psychogenic, or systemic disorders like chronic liver disease. Defective clearance of potential pruritogenic substances that activate itch-specific neurons innervating the skin is thought to contribute to cholestatic pruritus. However, because the underlying disease-specific pruritogens and itch-specific neuronal pathways and mechanism(s) are unknown, symptomatic therapeutic intervention often leads to no or only limited success. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a model for hepatic pruritus and then to evaluate the contribution of inflammation, peripheral neuronal sensitization, and specific signaling pathways and subpopulations of itch-responsive neurons to scratching behavior and thermal hypersensitivity. Chronic BDL rats displayed enhanced scratching behavior and thermal hyperalgesia indicative of peripheral neuroinflammation. BDL-induced itch and hypersensitivity involved a minor contribution of histaminergic/serotonergic receptors, but significant activation of protein-activated receptor 2 (PAR2) receptors, prostaglandin PGE2 formation, and potentiation of transient receptor potential vanilloid 1 (TRPV1) channel activity. The sensitization of dorsal root ganglion nociceptors in BDL rats was associated with increased surface expression of PAR2 and TRPV1 proteins and an increase in the number of PAR2- and TRPV1-expressing peptidergic neurons together with a shift of TRPV1 receptor expression to medium sized dorsal root ganglion neurons. These results suggest that pruritus and hyperalgesia in chronic cholestatic BDL rats are associated with neuroinflammation and involve PAR2-induced TRPV1 sensitization. Thus, pharmacological modulation of PAR2 and/or TRPV1 may be a valuable therapeutic approach for patients with chronic liver pruritus

  13. Potentiation of the Transient Receptor Potential Vanilloid 1 Channel Contributes to Pruritogenesis in a Rat Model of Liver Disease*

    PubMed Central

    Belghiti, Majedeline; Estévez-Herrera, Judith; Giménez-Garzó, Carla; González-Usano, Alba; Montoliu, Carmina; Ferrer-Montiel, Antonio; Felipo, Vicente; Planells-Cases, Rosa

    2013-01-01

    Persistent pruritus is a common disabling dermatologic symptom associated with different etiologic factors. These include primary skin conditions, as well as neuropathic, psychogenic, or systemic disorders like chronic liver disease. Defective clearance of potential pruritogenic substances that activate itch-specific neurons innervating the skin is thought to contribute to cholestatic pruritus. However, because the underlying disease-specific pruritogens and itch-specific neuronal pathways and mechanism(s) are unknown, symptomatic therapeutic intervention often leads to no or only limited success. In the current study, we aimed to first validate rats with bile duct ligation (BDL) as a model for hepatic pruritus and then to evaluate the contribution of inflammation, peripheral neuronal sensitization, and specific signaling pathways and subpopulations of itch-responsive neurons to scratching behavior and thermal hypersensitivity. Chronic BDL rats displayed enhanced scratching behavior and thermal hyperalgesia indicative of peripheral neuroinflammation. BDL-induced itch and hypersensitivity involved a minor contribution of histaminergic/serotonergic receptors, but significant activation of protein-activated receptor 2 (PAR2) receptors, prostaglandin PGE2 formation, and potentiation of transient receptor potential vanilloid 1 (TRPV1) channel activity. The sensitization of dorsal root ganglion nociceptors in BDL rats was associated with increased surface expression of PAR2 and TRPV1 proteins and an increase in the number of PAR2- and TRPV1-expressing peptidergic neurons together with a shift of TRPV1 receptor expression to medium sized dorsal root ganglion neurons. These results suggest that pruritus and hyperalgesia in chronic cholestatic BDL rats are associated with neuroinflammation and involve PAR2-induced TRPV1 sensitization. Thus, pharmacological modulation of PAR2 and/or TRPV1 may be a valuable therapeutic approach for patients with chronic liver pruritus

  14. Activation of EP4 receptors contributes to prostaglandin E2-mediated stimulation of renal sensory nerves.

    PubMed

    Kopp, Ulla C; Cicha, Michael Z; Nakamura, Kazuhiro; Nüsing, Rolf M; Smith, Lori A; Hökfelt, Tomas

    2004-12-01

    Induction of cyclooxygenase-2 (COX-2) in the renal pelvic wall increases prostaglandin E(2) (PGE(2)) leading to stimulation of cAMP production, which results in substance P (SP) release and activation of renal mechanosensory nerves. The subtype of PGE receptors involved, EP2 and/or EP4, was studied by immunohistochemistry and renal pelvic administration of agonists and antagonists of EP2 and EP4 receptors. EP4 receptor-like immunoreactivity (LI) was colocalized with calcitonin gene-related peptide (CGRP)-LI in dorsal root ganglia (DRGs) at Th(9)-L(1) and in nerve terminals in the renal pelvic wall. Th(9)-L(1) DRG neurons also contained EP3 receptor-LI and COX-2-LI, each of which was colocalized with CGRP-LI in some neurons. No renal pelvic nerves contained EP3 receptor-LI and only very few nerves COX-2-LI. The EP1/EP2 receptor antagonist AH-6809 (20 microM) had no effect on SP release produced by PGE(2) (0.14 microM) from an isolated rat renal pelvic wall preparation. However, the EP4 receptor antagonist L-161,982 (10 microM) blocked the SP release produced by the EP2/EP4 receptor agonist butaprost (10 microM) 12 +/- 2 vs. 2 +/- 1 and PGE(2), 9 +/- 1 vs. 1 +/- 0 pg/min. The SP release by butaprost and PGE(2) was similarly blocked by the EP4 receptor antagonist AH-23848 (30 microM). In anesthetized rats, the afferent renal nerve activity (ARNA) responses to butaprost 700 +/- 100 and PGE(2).780 +/- 100%.s (area under the curve of ARNA vs. time) were unaffected by renal pelvic perfusion with AH-6809. However, 1 microM L-161,982 and 10 microM AH-23848 blocked the ARNA responses to butaprost by 94 +/- 5 and 78 +/- 10%, respectively, and to PGE(2) by 74 +/- 16 and 74 +/- 11%, respectively. L-161,982 also blocked the ARNA response to increasing renal pelvic pressure 10 mmHg, 85 +/- 5%. In conclusion, PGE(2) increases renal pelvic release of SP and ARNA by activating EP4 receptors on renal sensory nerve fibers. PMID:15292051

  15. Type 3 muscarinic receptors contribute to intestinal mucosal homeostasis and clearance of Nippostrongylus brasiliensis through induction of TH2 cytokines.

    PubMed

    McLean, Leon P; Smith, Allen; Cheung, Lumei; Urban, Joseph F; Sun, Rex; Grinchuk, Viktoriya; Desai, Neemesh; Zhao, Aiping; Raufman, Jean-Pierre; Shea-Donohue, Terez

    2016-07-01

    Despite increased appreciation for the role of nicotinic receptors in the modulation of and response to inflammation, the contribution of muscarinic receptors to mucosal homeostasis, clearance of enteric pathogens, and modulation of immune cell function remains relatively undefined. Uninfected and Nippostrongylus brasiliensis-infected wild-type and type 3 muscarinic receptor (M3R)-deficient (Chrm3(-/-)) mice were studied to determine the contribution of M3R to mucosal homeostasis as well as host defense against the TH2-eliciting enteric nematode N. brasiliensis Intestinal permeability and expression of TH1/TH17 cytokines were increased in uninfected Chrm3(-/-) small intestine. Notably, in Chrm3(-/-) mice infected with N. brasiliensis, small intestinal upregulation of TH2 cytokines was attenuated and nematode clearance was delayed. In Chrm3(-/-) mice, TH2-dependent changes in small intestinal function including smooth muscle hypercontractility, increased epithelial permeability, decreased epithelial secretion and absorption, and goblet cell expansion were absent despite N. brasiliensis infection. These findings identify an important role for M3R in host defense and clearance of N. brasiliensis, and support the expanding role of cholinergic muscarinic receptors in maintaining mucosal homeostasis. PMID:27173511

  16. The cyclooxygenase-2 pathway via the PGE2 EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination

    PubMed Central

    Palumbo, Sara; Toscano, Christopher D.; Parente, Laura; Weigert, Roberto; Bosetti, Francesca

    2011-01-01

    Cyclooxygenases (COX)-1 and -2 are key enzymes required for the conversion of arachidonic acid (AA) to eicosanoids, potent mediators of inflammation. In patients with multiple sclerosis (MS), COX-2 derived prostaglandins (PGs) are elevated in the cerebrospinal fluid and COX-2 is upregulated in demyelinating plaques. However, it is not known whether COX-2 activity contributes to oligodendrocyte death. In cuprizone-induced demyelination, oligodendrocyte apoptosis and a concomitant increase in the gene expression of COX-2 and PGE2-EP2 receptor precede histological demyelination. COX-2 and EP2 receptor were expressed by oligodendrocytes, suggesting a causative role for the COX-2/EP2 pathway in the initiation of oligodendrocyte death and demyelination. COX-2 gene deletion, chronic treatment with the COX-2 selective inhibitor celecoxib, or with the EP2 receptor antagonist AH6809 reduced cuprizone-induced oligodendrocyte apoptosis, the degree of demyelination and motor dysfunction. These data indicate that the PGE2 EP2 receptor contributes to oligodendrocyte apoptosis and open possible new therapeutic approaches for MS. PMID:21699540

  17. Vitamin D Receptor Gene FokI Polymorphism Contributes to Increasing the Risk of Tuberculosis

    PubMed Central

    Huang, Liling; Liu, Cunxu; Liao, Guangfu; Yang, Xiaobing; Tang, Xiuwen; Chen, Jingjie

    2015-01-01

    Abstract The association between vitamin D receptor (VDR) FokI polymorphism and tuberculosis (TB) risk remains a matter of debate. Potential selection bias exists in most studies using HIV-positive TB patients. An update meta-analysis was carried out to derive a more reliable assessment of the association between FokI polymorphisms and TB risk, especially in HIV-negative TB patients. All major databases from inception to June 2015 were searched for all publications that studied the association between FokI polymorphism and TB risk. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated according to the frequencies of genotypes. In total, 32 studies with 4894 cases and 5319 controls were included in this meta-analysis. In the overall analysis, the estimated OR was 1.34 (95% CI=1.091–1.646, P = 0.005) in the best genetic model (recessive model, ff vs fF+FF) with moderate heterogeneity (I2 = 32.2%, P = 0.043). In the subgroup analysis stratified by HIV status, significant associations were found only in the HIV-negative TB group (OR = 1.60, 95% CI = 1.180–2.077, P = 0.002; I2 = 29.5%, and P = 0.141 for heterogeneity). In the subgroup analysis stratified by ethnicity, significant associations were found in the Asian group (OR = 1.65, 95% CI = 1.205–2.261, P = 0.002; I2 = 43.9%, and P = 0.024 for heterogeneity), but not in the Caucasian group (OR = 1.09, 95% CI = 0.762–1.547, P = 0.649; I2 = 0.0%, and P = 0.740 for heterogeneity) and African group (OR = 0.99, 95% CI = 0.726–1.341, P = 0.934; I2 = 43.9%, and P = 0.024 for heterogeneity). This meta-analysis confirms that VDR FokI polymorphism contributes to the risk of TB, especially in HIV-negative TB patients and in the Asian group. Further studies are required to clarify the role of the FokI polymorphism in HIV-positive TB and in other ethnic groups. PMID:26705207

  18. The contribution of endogenous benzodiazepine receptor ligands to the pathogenesis of hepatic encephalopathy

    SciTech Connect

    Basile, A.S. )

    1991-02-01

    The involvement of the gamma-aminobutyric acid A(GABAA) receptor complex in the pathogenesis of hepatic encephalopathy (HE) was examined in galactosamine-treated rabbits with HE caused by fulminant hepatic failure. Radioligand binding to the constituent components of the GABAA receptor complex was unchanged in rabbits with HE. However, partially purified extracts from encephalopathic rabbit brain were approximately three times more potent in inhibiting ({sup 3}H)Ro 15-1788 binding to benzodiazepine (BZ) receptors than extracts from control rabbits. The inhibition of radioligand binding to the BZ receptor produced by these extracts was competitive and reversible and was significantly enhanced by GABA. Further purification of these extracts by high-performance liquid chromatography (HPLC) indicated that the inhibitory activity was localized in several peaks, some of which had retention times corresponding to 1,4-benzodiazepine standards. The presence of diazepam in these extracts was confirmed using mass spectroscopy. Both mass spectroscopic and radiometric techniques demonstrated that the concentration of diazepam in brain extracts from encephalopathic rabbits was approximately 4 times greater than control extracts. These findings link the presence of BZ receptor agonists to the development of a neuropathological condition, thereby providing a rational basis for the use of BZ receptor antagonists in the management of HE in man.

  19. Functional Contribution of α3L8′ to the Neuronal Nicotinic α3 Receptor

    PubMed Central

    Nieves-Cintrón, Madeline; Caballero-Rivera, Daniel; Silva, Walter I.; Navedo, Manuel F.; Lasalde-Dominicci, José A.

    2015-01-01

    The role of position L8′, located in transmembrane domain 1 of the neuronal nicotinic α3 subunit, was characterized by using two-electrode voltage clamp in Xenopus oocytes. Four amino acids (Ala, Ser, Phe, and Tyr) were inserted at this conserved position, and the mutant subunit was coexpressed with either wild-type β2 or β4 subunits. These substitutions led to significant alterations in the pharmacodynamic parameters of cholinergic agents, resulting in loss of function. Ala and Ser substitutions resulted in losses in agonist (ACh, nicotine, and DMPP) potency and intrinsic activity at both α3β2 and α3β4 receptors. Similarly, significant changes in antagonist potency were produced by the Ala and Ser substitutions. Phe and Tyr mutations did not alter the receptor's EC50 for ACh or nicotine but reduced the EC50 for DMPP at both receptors. The Phe mutation also reduced the intrinsic activity of all agonists tested at both receptors. The Tyr mutation, though, led to a decrease in intrinsic activity for all agonists at the α3β2 receptor, yet resulted in no changes for DMPP, a decrease for nicotine, and an increase for ACh at the α3β4 receptor. The most dramatic changes in the receptor's functional properties were produced by substitutions that introduced the largest changes in amino acid volume. Additional replacements (Gly, Thr, and Val) suggested an inverse correlation between amino acid volume at position α3L8′ and EC50 for α3β4 nAChRs; however, α3β2 nAChRs displayed a nonlinear correlation. These data demonstrate that structural alterations at position α3L8′ could propagate to the agonist-binding site. PMID:18615639

  20. Nuclear orphan receptor Nor-1 contributes to depressive behavior in the Wistar-Kyoto rat model of depression.

    PubMed

    Schaffer, Daniel J; Tunc-Ozcan, Elif; Shukla, Pradeep K; Volenec, Andreja; Redei, Eva E

    2010-11-29

    The current study explored the effects of prolonged antidepressant treatment on mRNA levels of two nuclear receptors in specific brain regions of an animal model of depression, the Wistar-Kyoto (WKY) rat. Both nuclear receptors have been implicated in the development or treatment of depression. The expression of nuclear orphan receptor-1 (Nor-1), a member of the NR4A nuclear orphan receptor family, is induced by electroconvulsive shock, an effective treatment for depression. Deficit in the levels or function of the glucocorticoid receptor (GR) found in depressed patients has been causally implicated in depression, as this deficit is normalized by antidepressant treatments. Baseline levels of amygdalar Nor-1 and GR mRNA were higher in the WKYs compared to the comparison control Sprague-Dawley rats (SD). Prolonged treatment with the antidepressant desipramine (DMI) decreased the expression of both transcripts in the WKY strain concomitantly with decreased immobility in the forced swim test (FST) of depressive behavior. Using short hairpin RNA (shRNA) targeted against Nor-1, we investigated the direct contribution of elevated Nor-1 expression in the amygdala of WKY to their exaggerated depressive behavior in the FST. After validating the shRNA targeting of Nor-1 in vitro, Nor-1 shRNA containing vector was infused intracerebroventricularly, using a linear polyethylenimine (PEI)-containing in vivo gene delivery system. Repeated administration of Nor-1 shRNA ameliorated the depressive behavior of WKYs in the FST and decreased amygdalar Nor-1 mRNA levels without affecting GR mRNA levels. These data demonstrate that brain region-specific changes in GR expression in response to DMI are strain dependent and that elevated amygdalar Nor-1 expression can contribute to depressive behavior in the WKY model of depression. PMID:20851110

  1. Differential contributions of serotonin receptors to the behavioral effects of indoleamine hallucinogens in mice.

    PubMed

    Halberstadt, Adam L; Koedood, Liselore; Powell, Susan B; Geyer, Mark A

    2011-11-01

    Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT(2C) receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT(2A) receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT(1A) antagonist WAY-100635 but were not altered by the selective 5-HT(2C) antagonist SB 242,084 or by 5-HT(2A) receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT(2C) and 5-HT(1A) receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6-9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT(2A) sites but is inactive at the 5-HT(1A) receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin

  2. Contributions of protein kinases and β-arrestin to termination of protease-activated receptor 2 signaling

    PubMed Central

    Jung, Seung-Ryoung; Seo, Jong Bae; Deng, Yi; Asbury, Charles L.; Hille, Bertil

    2016-01-01

    Activated Gq protein–coupled receptors (GqPCRs) can be desensitized by phosphorylation and β-arrestin binding. The kinetics and individual contributions of these two mechanisms to receptor desensitization have not been fully distinguished. Here, we describe the shut off of protease-activated receptor 2 (PAR2). PAR2 activates Gq and phospholipase C (PLC) to hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol and inositol trisphosphate (IP3). We used fluorescent protein–tagged optical probes to monitor several consequences of PAR2 signaling, including PIP2 depletion and β-arrestin translocation in real time. During continuous activation of PAR2, PIP2 was depleted transiently and then restored within a few minutes, indicating fast receptor activation followed by desensitization. Knockdown of β-arrestin 1 and 2 using siRNA diminished the desensitization, slowing PIP2 restoration significantly and even adding a delayed secondary phase of further PIP2 depletion. These effects of β-arrestin knockdown on PIP2 recovery were prevented when serine/threonine phosphatases that dephosphorylate GPCRs were inhibited. Thus, PAR2 may continuously regain its activity via dephosphorylation when there is insufficient β-arrestin to trap phosphorylated receptors. Similarly, blockers of protein kinase C (PKC) and G protein–coupled receptor kinase potentiated the PIP2 depletion. In contrast, an activator of PKC inhibited receptor activation, presumably by augmenting phosphorylation of PAR2. Our interpretations were strengthened by modeling. Simulations supported the conclusions that phosphorylation of PAR2 by protein kinases initiates receptor desensitization and that recruited β-arrestin traps the phosphorylated state of the receptor, protecting it from phosphatases. Speculative thinking suggested a sequestration of phosphatidylinositol 4-phosphate 5 kinase (PIP5K) to the plasma membrane by β-arrestin to explain why knockdown of β-arrestin led to

  3. Glycine and GABAA receptors mediate tonic and phasic inhibitory processes that contribute to prepulse inhibition in the goldfish startle network

    PubMed Central

    Curtin, Paul C. P.; Preuss, Thomas

    2015-01-01

    Prepulse inhibition (PPI) is understood as a sensorimotor gating process that attenuates sensory flow to the startle pathway during early stages (20–1000 ms) of information processing. Here, we applied in vivo electrophysiology and pharmacology to determine if PPI is mediated by glycine receptors (GlyRs) and/or GABAA receptors (GABAARs) in the goldfish auditory startle circuit. Specifically, we used selective antagonists to dissect the contributions of target receptors on sound-evoked postsynaptic potentials (PSPs) recorded in the neurons that initiate startle, the Mauthner-cells (M-cell). We found that strychnine, a GlyR antagonist, disrupted a fast-activated (5 ms) and rapidly (<50 ms) decaying (feed-forward) inhibitory process that contributes to PPI at 20 ms prepulse/pulse inter-stimulus intervals (ISI). Additionally we observed increases of the evoked postsynaptic potential (PSP) peak amplitude (+87.43 ± 21.53%, N = 9) and duration (+204 ± 48.91%, N = 9). In contrast, treatment with bicuculline, a GABAAR antagonist, caused a general reduction in PPI across all tested interstimulus intervals (ISIs) (20–500 ms). Bicuculline also increased PSP peak amplitude (+133.8 ± 10.3%, N = 5) and PSP duration (+284.95 ± 65.64%, N = 5). Treatment with either antagonist also tonically increased post-synaptic excitability in the M-cells, reflected by an increase in the magnitude of antidromically-evoked action potentials (APs) by 15.07 ± 3.21%, N = 7 and 16.23 ± 7.08%, N = 5 for strychnine and bicuculline, respectively. These results suggest that GABAARs and GlyRs are functionally segregated to short- and longer-lasting sound-evoked (phasic) inhibitory processes that contribute to PPI, with the mediation of tonic inhibition by both receptor systems being critical for gain control within the M-cell startle circuit. PMID:25852486

  4. Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats.

    PubMed

    Ng, Melinda; Ndungo, Esther; Kaczmarek, Maria E; Herbert, Andrew S; Binger, Tabea; Kuehne, Ana I; Jangra, Rohit K; Hawkins, John A; Gifford, Robert J; Biswas, Rohan; Demogines, Ann; James, Rebekah M; Yu, Meng; Brummelkamp, Thijn R; Drosten, Christian; Wang, Lin-Fa; Kuhn, Jens H; Müller, Marcel A; Dye, John M; Sawyer, Sara L; Chandran, Kartik

    2015-01-01

    Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filovirus host range in nature. PMID:26698106

  5. NMDA Receptor Plasticity in the Hypothalamic Paraventricular Nucleus Contributes to the Elevated Blood Pressure Produced by Angiotensin II

    PubMed Central

    Wang, Gang; Coleman, Christal G.; Chan, June; Ogorodnik, Evgeny; Van Kempen, Tracey A.; Milner, Teresa A.; Butler, Scott D.; Young, Colin N.; Davisson, Robin L.; Iadecola, Costantino; Pickel, Virginia M.

    2015-01-01

    Hypertension induced by angiotensin II (Ang II) is associated with glutamate-dependent dysregulation of the hypothalamic paraventricular nucleus (PVN). Many forms of glutamate-dependent plasticity are mediated by NMDA receptor GluN1 subunit expression and the distribution of functional receptor to the plasma membrane of dendrites. Here, we use a combined ultrastructural and functional analysis to examine the relationship between PVN NMDA receptors and the blood pressure increase induced by chronic infusion of a low dose of Ang II. We report that the increase in blood pressure produced by a 2 week administration of a subpressor dose of Ang II results in an elevation in plasma membrane GluN1 in dendrites of PVN neurons in adult male mice. The functional implications of these observations are further demonstrated by the finding that GluN1 deletion in PVN neurons attenuated the Ang II-induced increases in blood pressure. These results indicate that NMDA receptor plasticity in PVN neurons significantly contributes to the elevated blood pressure mediated by Ang II. PMID:26134639

  6. GABAA Receptor in the Thalamic Specific Relay System Contributes to the Propofol-Induced Somatosensory Cortical Suppression in Rat

    PubMed Central

    Zhang, Yu; Wang, Chaoping; Zhang, Yi; Zhang, Lin; Yu, Tian

    2013-01-01

    Interaction with the gamma-aminobutyric-acid-type-A (GABAA) receptors is recognized as an important component of the mechanism of propofol, a sedative-hypnotic drug commonly used as anesthetic. However the contribution of GABAA receptors to the central nervous system suppression is still not well understood, especially in the thalamocortical network. In the present study, we investigated if intracerebral injection of bicuculline (a GABAA receptor antagonist) into the thalamus ventral posteromedial nucleus (VPM, a thalamus specific relay nuclei that innervated S1 mostly) could reverse propofol-induced cortical suppression, through recording the changes of both spontaneous and somatosensory neural activities in rat’s somatosensory cortex (S1). We found that after injection of bicuculline into VPM, significant increase of neural activities were observed in all bands of local field potentials (total band, 182±6%), while the amplitude of all components in somatosensory evoked potentials were also increased (negative, 121±9% and positive, 124±6%).These data support that the potentiation of GABAA receptor-mediated synaptic inhibition in a thalamic specific relay system seems to play a crucial role in propofol-induced cortical suppression in the somatosensory cortex of rats. PMID:24324778

  7. Contribution of the Middle Eastern dust source areas to PM10 levels in urban receptors: Case study of Tehran, Iran

    NASA Astrophysics Data System (ADS)

    Givehchi, Raheleh; Arhami, Mohammad; Tajrishy, Massoud

    2013-08-01

    The origins and evolution of the Middle Eastern dust storms which frequently impact the residents of this arid region were studied. A methodology was adapted and developed to identify the desert regions of potential dust sources and determine their contributions to PM10 concentrations in the highly-populated receptor city of Tehran, Iran. Initially, the episodes of regional dust intrusion and the resulting amounts of increase in the particulate concentrations during these episodes were determined using a statistical analyzing methodology. The dust episodes were also inspected with the aerosol index information from the Ozone Monitoring Instrument (OMI). The Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model was used as the main tool to determine the proportions of dust originating from different deserts during the dusty episodes of 2009-2010. Daily 5-day back trajectories were obtained from the receptor stations during the dust outbreaks in order to find and confirm the location of potential sources. After the boundaries of the potential sources were determined by 5-day backward trajectories, this region was divided into different areas to quantify their contributions to the measured PM10 levels. The proximity between the measured and simulated data confirmed the ability of HYSPLIT in modeling the Middle Eastern dust intrusion and estimating the particulate concentration in the downwind receptor sites. Results showed that the deserts in Iraq and Syria are the main contributing dust sources which comprise more than 90% of the dust related PM10 concentrations in Tehran, during the studied dust episodes. The sources in northern Iraq and eastern Syria respectively represented 44% and 32% contributions on average.

  8. Melatonin receptor signaling contributes to neuroprotection upon arousal from torpor in thirteen-lined ground squirrels.

    PubMed

    Schwartz, Christine; Ballinger, Mallory A; Andrews, Matthew T

    2015-11-15

    The brain of mammalian hibernators is naturally protected. Hibernating ground squirrels undergo rapid and extreme changes in body temperature and brain perfusion as they cycle between lengthy torpor bouts and brief periods of euthermia called interbout arousals (IBAs). Arousal from torpor to IBA occurs rapidly, but there is no evidence of brain injury accompanying this extreme physiological transition. Production of the hormone melatonin accompanies arousal, suggesting that it plays a protective role at this time. Here, we investigated mechanisms of melatonin receptor-mediated protection in the brain of the hibernating ground squirrel. We administered the competitive melatonin receptor antagonist luzindole (30 mg/kg ip) to ground squirrels at the predicted end of a torpor bout, triggering an arousal. We found that luzindole-treated animals exhibited caspase-3 activity two times higher than vehicle-treated animals in the hypothalamus at midarousal (P = 0.01), suggesting that melatonin receptor signaling is important for protection in this brain region. We also found a 30% decline in succinate-fueled mitochondrial respiration in luzindole-treated animals compared with vehicle-treated animals (P = 0.019), suggesting that melatonin receptor signaling is important for optimal mitochondrial function during arousal from torpor. The mitochondrial effects of luzindole treatment were seen only during the hibernation season, indicating that this effect is specifically important for arousal from torpor. These data provide evidence for the protective role of melatonin receptor signaling during the extreme physiological transition that occurs when a hibernating mammal arouses from torpor and provide further evidence for regional and seasonal changes in the hibernator brain. PMID:26354846

  9. Adenosine A1 Receptor-Mediated Endocytosis of AMPA Receptors Contributes to Impairments in Long-Term Potentiation (LTP) in the Middle-Aged Rat Hippocampus.

    PubMed

    Chen, Zhicheng; Stockwell, Jocelyn; Cayabyab, Francisco S

    2016-05-01

    Aging causes multiple changes in the mammalian brain, including changes in synaptic signaling. Previous reports have shown increased extracellular adenosine in the aging brain, and we recently reported that activation of adenosine A1 receptors (A1Rs) induces AMPA receptor (AMPAR) internalization in rat hippocampus. This study investigated whether aging-related changes in the rat hippocampus include altered surface expression of adenosine A1 and A2A receptors, and whether these changes correspond to changes in AMPAR surface expression and altered synaptic plasticity. We found reduced A1R surface expression in middle-aged rat hippocampus, and also reduced GluA1 and GluA2 AMPAR subunit surface expression. Using a chemically-induced LTP (cLTP) experimental protocol, we recorded fEPSPs in young (1 month old) and middle-aged (7-12 month old) rat hippocampal slices. There were significant impairments in cLTP in middle-aged slices, suggesting impaired synaptic plasticity. Since we previously showed that the A1R agonist N(6)-cyclopentyladenosine (CPA) reduced both A1Rs and GluA2/GluA1 AMPARs, we hypothesized that the observed impaired synaptic plasticity in middle-aged brains is regulated by A1R-mediated AMPAR internalization by clathrin-mediated endocytosis. Following cLTP, we found a significant increase in GluA1 and GluA2 surface expression in young rats, which was blunted in middle-aged brains or in young brains pretreated with CPA. Blocking A1Rs with 8-cyclopentyl-1,3-dipropylxanthine or AMPAR endocytosis with either Tat-GluA2-3Y peptide or dynasore (dynamin inhibitor) similarly enhanced AMPAR surface expression following cLTP. These data suggest that age-dependent alteration in adenosine receptor expression contributes to increased AMPAR endocytosis and impaired synaptic plasticity in aged brains. PMID:26700433

  10. Contribution of opioid and metabotropic glutamate receptor mechanisms to inhibition of bladder overactivity by tibial nerve stimulation.

    PubMed

    Matsuta, Yosuke; Mally, Abhijith D; Zhang, Fan; Shen, Bing; Wang, Jicheng; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2013-07-15

    The contribution of metabotropic glutamate receptors (mGluR) and opioid receptors to inhibition of bladder overactivity by tibial nerve stimulation (TNS) was investigated in cats under α-chloralose anesthesia using LY341495 (a group II mGluR antagonist) and naloxone (an opioid receptor antagonist). Slow infusion cystometry was used to measure the volume threshold (i.e., bladder capacity) for inducing a large bladder contraction. After measuring the bladder capacity during saline infusion, 0.25% acetic acid (AA) was infused to irritate the bladder, activate the nociceptive C-fiber bladder afferents, and induce bladder overactivity. AA significantly (P < 0.0001) reduced bladder capacity to 26.6 ± 4.7% of saline control capacity. TNS (5 Hz, 0.2 ms) at 2 and 4 times the threshold (T) intensity for inducing an observable toe movement significantly increased bladder capacity to 62.2 ± 8.3% at 2T (P < 0.01) and 80.8 ± 9.2% at 4T (P = 0.0001) of saline control capacity. LY341495 (0.1-5 mg/kg iv) did not change bladder overactivity, but completely suppressed the inhibition induced by TNS at a low stimulus intensity (2T) and partially suppressed the inhibition at high intensity (4T). Following administration of LY341495, naloxone (0.01 mg/kg iv) completely eliminated the high-intensity TNS-induced inhibition. However, without LY341495 treatment a 10 times higher dose (0.1 mg/kg) of naloxone was required to completely block TNS inhibition. These results indicate that interactions between group II mGluR and opioid receptor mechanisms contribute to TNS inhibition of AA-induced bladder overactivity. Understanding neurotransmitter mechanisms underlying TNS inhibition of bladder overactivity is important for the development of new treatments for bladder disorders. PMID:23576608

  11. Nerve injury-induced changes in Homer/glutamate receptor signaling contribute to the development and maintenance of neuropathic pain.

    PubMed

    Obara, Ilona; Goulding, Scott P; Hu, Jia-Hua; Klugmann, Matthias; Worley, Paul F; Szumlinski, Karen K

    2013-10-01

    While group 1 metabotropic glutamate receptors (mGluRs) and ionotropic N-methyl-d-aspartate (NMDA) receptors regulate nociception, the precise molecular mechanism(s) contributing to glutamate signaling in chronic pain remain unclear. Here we not only confirmed the key involvement of Homer proteins in neuropathic pain, but also distinguished between the functional roles for different Homer family members and isoforms. Chronic constriction injury (CCI) of the sciatic nerve induced long-lasting, time-dependent increases in the postsynaptic density expression of the constitutively expressed (CC) isoforms Homer1b/c and/or Homer2a/b in the spinal dorsal horn and supraspinal structures involved in nociception (prefrontal cortex, thalamus), that co-occurred with increases in their associated mGluRs, NR2 subunits of the NMDA receptor, and the activation of downstream kinases. Virus-mediated overexpression of Homer1c and Homer2b after spinal (intrathecal) virus injection exacerbated CCI-induced mechanical and cold hypersensitivity, however, Homer1 and Homer2 gene knockout (KO) mice displayed no changes in their neuropathic phenotype. In contrast, overexpression of the immediate early gene (IEG) Homer1a isoform reduced, while KO of Homer1a gene potentiated neuropathic pain hypersensitivity. Thus, nerve injury-induced increases in CC-Homers expression promote pain in pathological states, but IEG-Homer induction protects against both the development and maintenance of neuropathy. Additionally, exacerbated pain hypersensitivity in transgenic mice with reduced Homer binding to mGluR5 supports also an inhibitory role for Homer interactions with mGluR5 in mediating neuropathy. Such data indicate that nerve injury-induced changes in glutamate receptor/Homer signaling contribute in dynamic but distinct ways to neuropathic pain processing, which has relevance for the etiology of chronic pain symptoms and its treatment. PMID:23685007

  12. PDF receptor signaling in Drosophila contributes to both circadian and geotactic behaviors.

    PubMed

    Mertens, Inge; Vandingenen, Anick; Johnson, Erik C; Shafer, Orie T; Li, W; Trigg, J S; De Loof, Arnold; Schoofs, Liliane; Taghert, Paul H

    2005-10-20

    The neuropeptide Pigment-Dispersing Factor (PDF) is a principle transmitter regulating circadian locomotor rhythms in Drosophila. We have identified a Class II (secretin-related) G protein-coupled receptor (GPCR) that is specifically responsive to PDF and also to calcitonin-like peptides and to PACAP. In response to PDF, the PDF receptor (PDFR) elevates cAMP levels when expressed in HEK293 cells. As predicted by in vivo studies, cotransfection of Neurofibromatosis Factor 1 significantly improves coupling of PDFR to adenylate cyclase. pdfr mutant flies display increased circadian arrhythmicity, and also display altered geotaxis that is epistatic to that of pdf mutants. PDFR immunosignals are expressed by diverse neurons, but only by a small subset of circadian pacemakers. These data establish the first synapse within the Drosophila circadian neural circuit and underscore the importance of Class II peptide GPCR signaling in circadian neural systems. PMID:16242402

  13. Toll-Like Receptor 9 Contributes to Defense against Acinetobacter baumannii Infection

    PubMed Central

    Noto, Michael J.; Boyd, Kelli L.; Burns, William J.; Varga, Matthew G.; Peek, Richard M.

    2015-01-01

    Acinetobacter baumannii is a common nosocomial pathogen capable of causing severe diseases associated with significant morbidity and mortality in impaired hosts. Pattern recognition receptors, such as the Toll-like receptors (TLRs), play a key role in pathogen detection and function to alert the immune system to infection. Here, we examine the role for TLR9 signaling in response to A. baumannii infection. In a murine model of A. baumannii pneumonia, TLR9−/− mice exhibit significantly increased bacterial burdens in the lungs, increased extrapulmonary bacterial dissemination, and more severe lung pathology compared with those in wild-type mice. Following systemic A. baumannii infection, TLR9−/− mice have significantly increased bacterial burdens in the lungs, as well as decreased proinflammatory cytokine and chemokine production. These results demonstrate that TLR9-mediated pathogen detection is important for host defense against the opportunistic pathogen Acinetobacter baumannii. PMID:26238713

  14. Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis*

    PubMed Central

    Sophocleous, Antonia; Marino, Silvia; Logan, John G.; Mollat, Patrick; Ralston, Stuart H.; Idris, Aymen I.

    2015-01-01

    The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing. PMID:26195631

  15. Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis.

    PubMed

    Sophocleous, Antonia; Marino, Silvia; Logan, John G; Mollat, Patrick; Ralston, Stuart H; Idris, Aymen I

    2015-09-01

    The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing. PMID:26195631

  16. The Polyomaviridae: Contributions of virus structure to our understanding of virus receptors and infectious entry

    SciTech Connect

    Neu, Ursula; Stehle, Thilo Atwood, Walter J.

    2009-02-20

    This review summarizes the field's major findings related to the characterization of polyomavirus structures and to the characterization of virus receptors and mechanisms of host cell invasion. The four members of the family that have received the most attention in this regard are the mouse polyomavirus (mPyV), the monkey polyomavirus SV40, and the two human polyomaviruses, JCV and BKV. The structures of both the mPyV and SV40 alone and in complex with receptor fragments have been solved to high resolution. The majority of polyomaviruses recognize terminal sialic acid in either an {alpha}2,3 linkage or an {alpha}2,6 linkage to the underlying galactose. Studies on virus structure, receptor utilization and mechanisms of entry have led to new insights into how these viruses interact in an active way with cells to ensure the nuclear delivery and expression of their genomes. Critical work on virus entry has led to the discovery of a pH neutral endocytic compartment that accepts cargo from caveolae and to novel roles for endoplasmic reticulum (ER) associated factors in virus uncoating and penetration of ER membranes. This review will summarize the major findings and compare and contrast the mechanisms used by these viruses to infect cells.

  17. Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats

    PubMed Central

    Ng, Melinda; Ndungo, Esther; Kaczmarek, Maria E; Herbert, Andrew S; Binger, Tabea; Kuehne, Ana I; Jangra, Rohit K; Hawkins, John A; Gifford, Robert J; Biswas, Rohan; Demogines, Ann; James, Rebekah M; Yu, Meng; Brummelkamp, Thijn R; Drosten, Christian; Wang, Lin-Fa; Kuhn, Jens H; Müller, Marcel A; Dye, John M; Sawyer, Sara L; Chandran, Kartik

    2015-01-01

    Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filovirus host range in nature. DOI: http://dx.doi.org/10.7554/eLife.11785.001 PMID:26698106

  18. Dissociable hippocampal and amygdalar D1-like receptor contribution to discriminated Pavlovian conditioned approach learning.

    PubMed

    Andrzejewski, Matthew E; Ryals, Curtis

    2016-02-15

    Pavlovian conditioning is an elementary form of reward-related behavioral adaptation. The mesolimbic dopamine system is widely considered to mediate critical aspects of reward-related learning. For example, initial acquisition of positively-reinforced operant behavior requires dopamine (DA) D1 receptor (D1R) activation in the basolateral amygdala (BLA), central nucleus of the amygdala (CeA), and the ventral subiculum (vSUB). However, the role of D1R activation in these areas on appetitive, non-drug-related, Pavlovian learning is not currently known. In separate experiments, microinfusions of the D1-like receptor antagonist SCH-23390 (3.0 nmol/0.5 μL per side) into the amygdala and subiculum preceded discriminated Pavlovian conditioned approach (dPCA) training sessions. D1-like antagonism in all three structures impaired the acquisition of discriminated approach, but had no effect on performance after conditioning was asymptotic. Moreover, dissociable effects of D1-like antagonism in the three structures on components of discriminated responding were obtained. Lastly, the lack of latent inhibition in drug-treated groups may elucidate the role of D1-like in reward-related Pavlovian conditioning. The present data suggest a role for the D1 receptors in the amygdala and hippocampus in learning the significance of conditional stimuli, but not in the expression of conditional responses. PMID:26632336

  19. Angiotensin receptor agonistic autoantibody-mediated TNF-α induction contributes to increased soluble endoglin production in preeclampsia

    PubMed Central

    Zhou, Cissy Chenyi; Irani, Roxanna A.; Zhang, Yujin; Blackwell, Sean; Mi, Tiejuan; Wen, Jiaming; Shelat, Harnath; Geng, Yong-Jian; Ramin, Susan M.; Kellems, Rodney E.; Xia, Yang

    2010-01-01

    Background Preeclampsia (PE) is a prevalent life-threatening hypertensive disorder of pregnancy. The circulating antiangiogenic factor, soluble endoglin (sEng), is elevated in the blood circulation of women with PE and contributes to disease pathology. However, the underlying mechanisms responsible for its induction in PE are unknown. Methods and Results Here we discovered that a circulating autoantibody, the angiotensin receptor agonistic autoantibody (AT1-AA), stimulates sang production via AT1 angiogenesis receptor activation in pregnant mice but not non-pregnant mice. Subsequently we demonstrate that the placenta is a major source contributing to sang induction in vivo and AT1-AA injected pregnant mice display the impaired placental angiogenesis. Using drug screening, we identified TNF-α as a circulating factor increased in the serum of autoantibody-injected pregnant mice contributing to AT1-AA-mediated sang induction in human umbilical vascular endothelial cells (HUVECs). Subsequently, among all the drugs screened we found that hemin, an inducer of heme oxygenase-1 (HO-1), functions as a break to control AT1-AA mediated sang induction by suppressing TNF-α signaling in Havocs. Finally, we demonstrated that AT1-AA-mediated decreased angiogenesis seen in human placenta villous explants was attenuated by TNF-α neutralizing antibodies, soluble TNF-α receptors and hemi, an inducer of home oxygenase, by abolishing both sang and sFlt-1 induction. Conclusions Our findings demonstrate that AT1-AA-mediated TNF-α induction, by overcoming its negative regulator, HO-1, is a key underlying mechanism responsible for impaired placenta angiogenesis by inducing both sEng and sFlt-1 secretion from human villous explants and provide important new targets for diagnosis and therapeutic intervention in the management of PE. PMID:20065159

  20. Endothelin B receptor contribution to peripheral microvascular function in women with polycystic ovary syndrome

    PubMed Central

    Wenner, Megan M; Taylor, Hugh S; Stachenfeld, Nina S

    2011-01-01

    Abstract Endothelin-1 is elevated in women with polycystic ovary syndrome (PCOS), and may play a role in the endothelial dysfunction associated with PCOS. Endothelin-1 binds two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). We hypothesized that ET-A mediates vasoconstriction in the cutaneous microvasculature in women with and without PCOS. We further hypothesized that while the ET-B receptors mediate vasodilatation in both groups of women, this response would be blunted in women with PCOS. During local skin warming, we used laser Doppler flowmetry combined with intradermal microdialysis to measure skin blood flow (SkBF) during graded ET-A (BQ-123) and ET-B (BQ-788) antagonist infusions in women with (n = 6) and without (n = 8) PCOS. In both groups, SkBF increased during local heating. The percentage of maximal SkBF–[BQ123] sigmoidal dose–response curve indicated a vasodilatory response as the concentration of the antagonist increased (Hill slope 4.96 ± 4.77, 4.74 ± 5.01; logED50 2.53 ± 0.09, 2.49 ± 0.09 nm, for PCOS and Control, respectively). In contrast, the % max SkBF–[BQ788] curve indicated a vasoconstrictive response (Hill slope –4.69 ± 3.85, –4.03 ± 3.85; logED50, 2.56 ± 0.09, 2.41 ± 0.12 nm, in PCOS and Control). Moreover, the SkBF–[BQ788] curve shifted to the right in women with PCOS, suggesting attenuated ET-B receptor mediated vasodilatation during local skin warming compared to Controls. Thus, the endothelium located ET-B receptors function similarly in women with and without PCOS, although with blunted responsiveness in women with PCOS. Our studies suggest that the lower ET-B receptor responsiveness associated with PCOS may reflect lower endothelial-mediated vasodilatation independent of generally lower vascular reactivity. PMID:21825025

  1. Effects of xanthine derivatives in a light/dark test in mice and the contribution of adenosine receptors.

    PubMed

    Imaizumi, M; Miyazaki, S; Onodera, K

    1994-11-01

    We investigated the effects of adenosine receptor antagonists, caffeine, theophylline, 8-phenyltheophylline, and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), in a light/dark test in mice. All antagonists decreased the time spent in the light zone in this test, which suggested that these compounds have anxiogenic effects. The anxiogenic effects of theophylline were reduced by pretreatment with CGS 21680, an A2-selective agonist, but not by N6-cyclopentyladenosine (CPA), an A1-selective agonist. However, the antagonism of the theophylline-induced anxiogenic effects by CGS21680 was only observed in the time spent in the light zone, and DPCPX-induced anxiogenic effects were neither reversed by CGS 21680 nor by CPA. Finally, it is notable that xanthine-derived adenosine antagonists tested here commonly showed anxiogenic effects in the light/dark test in mice. It is suggested that there is a minor contribution of adenosine receptors to these effects, although theophylline-induced anxiogenic effects were antagonized by an A2 receptor agonist. PMID:7746025

  2. Toll-like receptor 4 contributes to the inhibitory effect of morphine on colonic motility in vitro and in vivo.

    PubMed

    Farzi, Aitak; Halicka, Juraj; Mayerhofer, Raphaela; Fröhlich, Esther E; Tatzl, Eva; Holzer, Peter

    2015-01-01

    Opioids rank among the most potent analgesic drugs but gastrointestinal side effects, especially constipation, limit their therapeutic utility. The adverse effects of opioids have been attributed to stimulation of opioid receptors, but emerging evidence suggests that opioids interact with the innate immune receptor Toll-like receptor 4 (TLR4) and its signalling pathway. As TLR4 signalling affects gastrointestinal motility, we examined the involvement of TLR4 in morphine-induced depression of peristaltic motility in the guinea-pig intestine in vitro and male C57BL/6N mice in vivo. While the TLR4 antagonist TAK-242 (0.1 μM and 1 μM) did not alter the morphine-induced inhibition of peristalsis in the isolated guinea-pig small intestine, the morphine-induced decrease in pellet propulsion velocity in colonic segments was attenuated by TAK-242 (0.1 μM). The ability of TAK-242 (4 mg/kg) to mitigate the morphine-induced suppression of colonic motility was replicated in mice in vivo by measuring the expulsion time of beads inserted in the distal colon. The inhibition of upper gastrointestinal transit of mice by morphine was not affected by pre-treatment with TAK-242 (4 mg/kg) in vivo. This is the first report that morphine-induced inhibition of colonic peristalsis is alleviated by TLR4 antagonism. We therefore conclude that TLR4 may contribute to opioid-induced constipation. PMID:25962524

  3. Complement Receptor 1 Genetic Variants Contribute to the Susceptibility to Gastric Cancer in Chinese Population

    PubMed Central

    Zhao, Lina; Zhang, Zhi; Lin, Jia; Cao, Lei; He, Bing; Han, Sugui; Zhang, Xuemei

    2015-01-01

    As the receptor for C3b/C4b, type 1 complement receptor (CR1/CD35) plays an important role in the regulation of complement activity and is further involved in carcinogenesis. This study aimed to elucidate the association of CR1 genetic variants with the susceptibility to gastric cancer in Chinese population. Based on the NCBI database, totally 13 tag single nucleotide polymorphisms (SNPs) were selected by Haploview program and genotyped using iPlex Gold Genotyping Assay and Sequenom MassArray among 500 gastric cancer cases and 500 healthy controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression to evaluate the association of each SNP with gastric cancer. Of all selected Tag SNPs , CR1 rs9429942 T > C was found to confer to the risk of developing gastric cancer. Compared with the carriers with rs9429942 TT genotype, those with CT genotype had 88% decreased risk of developing gastric cancer with OR (95%CI) of 0.12 (0.03-0.50). Generalized multifactor dimensionality reduction (GMDR) analysis revealed a significant three-way interaction among rs75422544 C > A, rs10494885 C > T and rs7525160 G > C in the development of gastric cancer with a maximum testing balance accuracy of 56.07% and a cross-validation consistency of 7/10 (P = 0.011). In conclusion, our findings demonstrated the genetic role of CR1 gene in the development of gastric cancer in Chinese population. PMID:26000043

  4. The active contribution of Toll-like receptors to allergic airway inflammation.

    PubMed

    Chen, Keqiang; Xiang, Yi; Yao, Xiaohong; Liu, Ying; Gong, Wanghua; Yoshimura, Teizo; Wang, Ji Ming

    2011-10-01

    Epithelia lining the respiratory tract represent a major portal of entry for microorganisms and allergens and are equipped with innate and adaptive immune signaling receptors for host protection. These include Toll-like receptors (TLRs) that recognize microbial components and evoke diverse responses in cells of the respiratory system. TLR stimulation by microorganism-derived molecules activates antigen presenting cells, control T helper (Th) 1, Th2, and Th17 immune cell differentiation, cytokine production by mast cells, and activation of eosinophils. It is clear that TLR are involved in the pathophysiology of allergic airway diseases such as asthma. Dendritic cells (DCs), a kind of antigen presenting cells, which play a key role in the induction of allergic airway inflammation, are privileged targets for pathogen associated molecular patterns (PAMPs). During the allergic responses, engagement of TLRs on DCs determines the Th2 polarization of the T cells. TLR signaling in mast cells increases the release of IL-5, and TLR activation of airway epithelial cells forces the generation of proallergic Th2 type of cytokines. Although these responses aim to protect the host, they may also result in inflammatory tissue damage in the airway. Under certain conditions, stimulation of TLRs, in particular, TLR9, may reduce Th2-dependent allergic inflammation by induction of Th1 responses. Therefore, understanding the complex regulatory roles of TLRs in the pathogenesis of allergic airway inflammation should facilitate the development of preventive and therapeutic measures for asthmatic patients. PMID:21624504

  5. Effect of low-intensity focused ultrasound on endothelin-1, nitrogen monoxide and oxytocin receptor in the uterine tissues of Sprague-Dawley rats following abortion

    PubMed Central

    ZHANG, YANXIA; GUO, JUFANG; LIN, CHUAN; LU, LU; LI, CHENGZHI

    2016-01-01

    The aim of the present study was to investigate the effect of low-intensity focused ultrasound on endothelin-1 (ET-1), nitrogen monoxide (NO) and oxytocin receptor (OXTR) levels in the uterine tissues of Sprague-Dawley (SD) rats following abortion. A total of 30 SD rats undergoing complete abortion were randomly divided into ultrasound irradiation and sham irradiation groups (15 rats per group). The rats in the ultrasound irradiation group were treated with low-intensity ultrasound (sound intensity, 2 W/cm2; frequency, 0.8 MHz) for 30 min daily for 5 consecutive days, and those in the sham irradiation group received sham treatment. The uterine tissue was removed to measure the levels of ET-1, NO and OXTR using the enzyme-linked immunosorbent assay and immunohistochemistry, respectively. The ET-1 level in the uterine tissues was significantly higher in the ultrasound irradiation group compared to the sham irradiation group (P<0.05); however, the NO level was similar in the 2 groups (P>0.05). In the uterine myometrium and endometrium, the strong positive expression of OXTR was observed in the ultrasound irradiation group, which was significantly higher compared to the sham irradiation group (P<0.05). Low-intensity ultrasound could promote uterine involution by increasing ET-1 levels, modifying the balance of ET-1 and NO, and enhancing the expression of OXTR in the uterine myometrium and endometrium. PMID:26998272

  6. The moderating role of an oxytocin receptor gene polymorphism in the relation between unsupportive social interactions and coping profiles: implications for depression

    PubMed Central

    McInnis, Opal A.; McQuaid, Robyn J.; Matheson, Kimberly; Anisman, Hymie

    2015-01-01

    Oxytocin is a hormone that is thought to influence prosocial behaviors and may be important in modulating responses to both positive and negative social interactions. Indeed, a single nucleotide polymorphism, rs53576, of the oxytocin receptor gene (OXTR) has been associated with decreased trust, empathy, optimism, and social support seeking, which are important components of coping with stressors. In the current study, conducted among undergraduate students (N = 225), it was shown that parental and peer social support was related to fewer depressive symptoms through elevated problem-focused coping and lower emotion-focused coping, and these effects were independent of the OXTR polymorphism. Unsupportive social interactions from parents were associated with more severe depressive symptoms through the greater use of emotion-focused coping, and this relation was moderated by the OXTR genotype. Specifically, individuals who carried the polymorphism on one or both of their alleles demonstrated increased emotion-focused coping following unsupportive responses compared to those without the polymorphism. Likewise, lower problem-focused coping mediated the relation between parental and peer unsupportive responses to depressive symptoms, but this mediated relation was only evident among carriers of the polymorphism. These findings suggest that carrying this OXTR polymorphism might favor disadvantageous coping styles in the face of negative social interactions, which in turn are linked to poor mood. Regardless of genotype, parental, and peer social support are fundamental in determining stress-related coping and well-being. PMID:26321972

  7. Surface-expressed insulin receptors as well as IGF-I receptors both contribute to the mitogenic effects of human insulin and its analogues.

    PubMed

    Lundby, Anders; Bolvig, Pernille; Hegelund, Anne Charlotte; Hansen, Bo F; Worm, Jesper; Lützen, Anne; Billestrup, Nils; Bonnesen, Christine; Oleksiewicz, Martin B

    2015-07-01

    There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF-I receptors (IGF-IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF-I caused phosphorylation of the IR as well as IGF-IR. Insulin exhibited mitogenicity EC(50) values in the single-digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF-IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA-mediated knockdown of IR and IGF-IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF-IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF-IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF-I in cells expressing more IR than IGF-IR, the hyper-mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper-mitogenic effect of X10 involves the IR as well as the IGF-IR. These results are relevant for preclinical safety assessment of developmental insulin analogues. PMID:25413577

  8. Contribution of different classes of glutamate receptors in the corticostriatal polysynaptic responses from striatal direct and indirect projection neurons

    PubMed Central

    2013-01-01

    responses that contribute to plateau depolarizations. Conclusions As it has been established in previous physiological studies in vivo, synaptic invasion over different latencies, spanning hundreds of milliseconds after a single stimulus strongly indicates convergent polysynaptic activation. Interconnected cortical neurons converging on the same SPNs may explain prolonged corticostriatal responses. Glutamate receptors participation in these responses is described as well as differences and similarities between dSPNs and iSPNs. PMID:23782743

  9. Peripheral and central P2X3 receptor contributions to colon mechanosensitivity and hypersensitivity in the mouse

    PubMed Central

    Shinoda, Masamichi; Feng, Bin; Gebhart, G. F.

    2009-01-01

    Background & Aims Irritable bowel syndrome is characterized by altered sensory qualities, namely discomfort/pain and colorectal hypersensitivity. In mice, we examined the role of P2X3 receptors in colon mechanosensitivity and intracolonic zymosan-produced hypersensitivity, a model of persistent colon hypersensitivity without colon inflammation. Methods The visceromotor response (VMR) to colon distension (15 – 60 mmHg) was determined before and after intracolonic saline or zymosan (30 mg/mL, 0.1 mL, daily for 3 days) treatment. Colon pathology and intracolonic ATP release was assessed in parallel experiments. To examine P2X3 receptor contributions to colon mechanosensation and hypersensitivity, electrophysiological experiments were performed using an in vitro colon-pelvic nerve preparation. Results VMRs to distension were significantly reduced in P2X3+/−and P2X3−/− mice relative to wildtype mice. Colon hypersensitivity produced by zymosan was virtually absent in P2X3−/− relative to wildtype or P2X3+/− mice. Intralumenal release of the endogenous P2X receptor ligand ATP did not differ between wildtype and P2X3−/− mice or change after intracolonic zymosan treatment. Responses of muscular and muscular-mucosal pelvic nerve afferents to mechanical stretch did not differ between P2X3−/− and wildtype mice. Both muscular and muscular-mucosal afferents in wildtype mice sensitized to application of an inflammatory soup, whereas only muscular-mucosal afferents did so in P2X3−/− mice. Conclusions These results suggest differential roles for peripheral and central P2X3 receptors in colon mechanosensory transduction and hypersensitivity. PMID:19549524

  10. Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells.

    PubMed

    Kashiwagi, Eiji; Shiota, Masaki; Yokomizo, Akira; Itsumi, Momoe; Inokuchi, Junichi; Uchiumi, Takeshi; Naito, Seiji

    2013-06-01

    Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally, EP3 (PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer. PMID:23493387

  11. Preferred recycling pathway by internalized PGE2 EP4 receptor following agonist stimulation in cultured dorsal root ganglion neurons contributes to enhanced EP4 receptor sensitivity.

    PubMed

    St-Jacques, Bruno; Ma, Weiya

    2016-06-21

    Prostaglandin E2 (PGE2), a well-known pain mediator abundantly produced in injured tissues, sensitizes nociceptive dorsal root ganglion (DRG) neurons (nociceptors) through its four EP receptors (EP1-4). Our prior study showed that PGE2 or EP4 agonist stimulates EP4 externalization and this event was not only suppressed by the inhibitor of anterograde export, but also by the recycling inhibitor (St-Jacques and Ma, 2013). These data suggest that EP4 recycling also contributes to agonist-enhanced EP4 surface abundance. In the current study, we tested this hypothesis using antibody-feeding-based internalization assay, recycling assay and FITC-PGE2 binding assay. We observed that selective EP4 agonist 1-hydroxy-PGE1 (1-OH-PGE1) or CAY10850 time- and concentration-dependently increased EP4 internalization in cultured DRG neuron. Internalized EP4 was predominantly localized in the early endosomes and recycling endosomes, but rarely in the late endosomes and lysosomes. These observations were confirmed by FITC-PGE2 binding assay. We further revealed that 1-OH-PGE1 or CAY10850 time- and concentration-dependently increased EP4 recycling. Double exposures to 1-OH-PGE1 induced a greater increase in calcitonin gene-related peptide (CGRP) release than a single exposure or vehicle exposure, an event blocked by pre-treatment with the recycling inhibitor monensin. Our data suggest that EP4 recycling contributes to agonist-induced cell surface abundance and consequently enhanced receptor sensitivity. Facilitating EP4 externalization and recycling is a novel mechanism underlying PGE2-induced nociceptor sensitization. PMID:27060485

  12. Autophagy downregulation contributes to insulin resistance mediated injury in insulin receptor knockout podocytes in vitro

    PubMed Central

    Xin, Wei; Li, Zhaoping; Chen, Liyong

    2016-01-01

    It is unknown whether autophagy activity is altered in insulin resistant podocytes and whether autophagy could be a therapeutic target for diabetic nephropathy (DN). Here we used shRNA transfection to knockdown the insulin receptor (IR) gene in cultured human immortalized podocytes as an in vitro insulin resistant model. Autophagy related proteins LC3, Beclin, and p62 as well as nephrin, a podocyte injury marker, were assessed using western blot and immunofluorescence staining. Our results show that autophagy is suppressed when podocytes lose insulin sensitivity and that treatment of rapamycin, an mTOR specific inhibitor, could attenuate insulin resistance induced podocytes injury via autophagy activation. The present study deepens our understanding of the role of autophagy in the pathogenesis of DN. PMID:27077005

  13. Contribution of Primary Afferent Input to Trigeminal Astroglial Hyperactivity, Cytokine Induction and NMDA Receptor Phosphorylation.

    PubMed

    Wang, H; Guo, W; Yang, K; Wei, F; Dubner, R; Ren, K

    2010-03-01

    We tested the hypothesis that primary afferent inputs play a role in astroglial hyperactivity after tissue injury. We first injected complete Freund's adjuvant (CFA, 0.05 ml, 1:1 oil/saline) into the masseter muscle, which upregulated glial fibrillary acidic protein (GFAP), a marker of astrocytes, interleukin (IL)-1β an inflammatory cytokine, and phosphorylation of serine896 of the NR1 subunit (P-NR1) of the NMDA receptor in the subnuclei interpolaris/caudalis (Vi/Vc) transition zone, an important structure for processing trigeminal nociceptive input. Local anesthetic block with lidocaine (2%) of the masseter muscle at 10 min prior to injection of CFA into the same site significantly reduced the CFA-induced increase in GFAP, IL-1β and P-NR1 (p<0.05, n=4/group). We then tested the effect of peripheral electrical stimulation (ES). The ES protocol was burst stimulation consisting of trains of 4 square pulses (10-100 Hz, 0.1-3 mA, 0.5 ms pulse width). Under pentobarbital anesthesia, an ES was delivered every 0.2 s for a total of 30 min. The Vi/Vc tissues were processed for immunohistochemistry or western blot analysis at 10-120 min after ES. Compared to naive and SHAM-treated rats, there was increased immunoreactivity against GFAP, IL-1β and P-NR1 in the Vi/Vc in rats receiving ES. Double staining showed that IL-1β was selectively localized in GFAP-positive astroglia, and P-NR1-immunoreactivity was localized to neurons. These findings indicate that primary afferent inputs are necessary and sufficient to induce astroglial hyperactivity and upregulation of IL-1β, as well as neuronal NMDA receptor phosphorylation. PMID:21170295

  14. Contribution of leptin receptor N-linked glycans to leptin binding.

    PubMed

    Kamikubo, Yuichi; Dellas, Claudia; Loskutoff, David J; Quigley, James P; Ruggeri, Zaverio M

    2008-03-15

    The extracellular domain of the human leptin receptor (Ob-R) contains 20 potential N-glycosylation sites whose role in leptin binding remains to be elucidated. We found that a mammalian cell-expressed sOb-R (soluble Ob-R) fragment (residues 22-839 of the extracellular domain) bound leptin with a dissociation constant of 1.8 nM. This binding was inhibited by Con A (concanavalin A) or wheatgerm agglutinin. Treatment of sOb-R with peptide N-glycosidase F reduced leptin binding by approximately 80% concurrently with N-linked glycan removal. The human megakaryoblastic cell line, MEG-01, expresses two forms of the Ob-R, of approx. 170 and 130 kDa molecular mass. Endo H (endoglycosidase H) treatment and cell culture with alpha-glucosidase inhibitors demonstrated that N-linked glycans are of the complex mature type in the 170 kDa form and of the high-mannose type in the 130 kDa form. Both isoforms bound leptin, but not after peptide N-glycosidase F treatment. An insect-cell-expressed sOb-R fragment, consisting of the Ig (immunoglobulin), CRH2 (second cytokine receptor homology) and FNIII (fibronectin type III) domains, bound leptin with affinity similar to that of the entire extracellular domain, but this function was abolished after N-linked glycan removal. The same treatment had no effect on the leptin-binding activity of the isolated CRH2 domain. Our findings show that N-linked glycans within Ig and/or FNIII domains regulate Ob-R function, but are not involved in essential interactions with the ligand. PMID:17983356

  15. Low renal mineralocorticoid receptor expression at birth contributes to partial aldosterone resistance in neonates

    PubMed Central

    Martinerie, Laetitia; Viengchareun, Say; Delezoïde, Anne-Lise; Jaubert, Francis; Sinico, Martine; Prevot, Sophie; Boileau, Pascal; Meduri, Géri; Lombès, Marc

    2009-01-01

    The human neonatal period is characterized by renal immaturity with impaired capacity to regulate water and sodium homeostasis, resembling partial aldosterone resistance. Since aldosterone effects are mediated by the mineralocorticoid receptor (MR), we postulated that this hormonal unresponsiveness could be related to low MR expression in the distal nephron. We measured aldosterone and renin levels in umbilical cord blood of healthy newborns. We used qPCR and immunohistochemistry to analyze the expression of MR and key players of the mineralocorticoid signaling pathway, during human and mouse renal development. High aldosterone and renin levels were found at birth. MR mRNA was detected in mouse kidney at day 16 postcoitum (E16), peaking at E18, but its expression was surprisingly very low at birth, rising progressively afterwards. Similar biphasic temporal expression was observed during human renal embryogenesis, with a transient expression between 15 and 24 weeks of gestation but an undetectable immunoreactive MR in late gestational and neonatal kidneys. This cyclic MR expression was tightly correlated with the evolution of the 11β–hydroxysteroid dehydrogenase type 2 and the epithelial sodium channel α-subunit. In contrast, glucocorticoid and vasopressin receptors, and aquaporin 2 followed a progressive and sustained evolution during renal maturation. Our study provides first evidence for a low renal MR expression level at birth, despite high aldosterone levels, which could account for compromised postnatal sodium handling. Elucidation of regulatory mechanisms governing MR expression should lead to new strategies for the management of sodium waste in preterms and neonates. PMID:19477942

  16. Dissociation between neural and vascular responses to sympathetic stimulation : contribution of local adrenergic receptor function

    NASA Technical Reports Server (NTRS)

    Jacob, G.; Costa, F.; Shannon, J.; Robertson, D.; Biaggioni, I.

    2000-01-01

    Sympathetic activation produced by various stimuli, eg, mental stress or handgrip, evokes regional vascular responses that are often nonhomogeneous. This phenomenon is believed to be the consequence of the recruitment of differential central neural pathways or of a sympathetically mediated vasodilation. The purpose of this study was to determine whether a similar heterogeneous response occurs with cold pressor stimulation and to test the hypothesis that local differences in adrenergic receptor function could be in part responsible for this diversity. In 8 healthy subjects, local norepinephrine spillover and blood flow were measured in arms and legs at baseline and during sympathetic stimulation induced by baroreflex mechanisms (nitroprusside infusion) or cold pressor stimulation. At baseline, legs had higher vascular resistance (27+/-5 versus 17+/-2 U, P=0.05) despite lower norepinephrine spillover (0.28+/-0.04 versus 0.4+/-0.05 mg. min(-1). dL(-1), P=0.03). Norepinephrine spillover increased similarly in both arms and legs during nitroprusside infusion and cold pressor stimulation. On the other hand, during cold stimulation, vascular resistance increased in arms but not in legs (20+/-9% versus -7+/-4%, P=0.03). Increasing doses of isoproterenol and phenylephrine were infused intra-arterially in arms and legs to estimate beta-mediated vasodilation and alpha-induced vasoconstriction, respectively. beta-Mediated vasodilation was significantly lower in legs compared with arms. Thus, we report a dissociation between norepinephrine spillover and vascular responses to cold stress in lower limbs characterized by a paradoxical decrease in local resistance despite increases in sympathetic activity. The differences observed in adrenergic receptor responses cannot explain this phenomenon.

  17. Nicotinic Acetylcholine Receptors containing the α6 subunit contribute to ethanol activation of ventral tegmental area dopaminergic neurons

    PubMed Central

    Liu, Liwang; Zhao-Shea, Rubing; McIntosh, J. Michael; Tapper, Andrew R.

    2013-01-01

    Nicotine and alcohol are often co-abused suggesting a common mechanism of action may underlie their reinforcing properties. Both drugs acutely increase activity of ventral tegmental area (VTA) dopaminergic (DAergic) neurons, a phenomenon associated with reward behavior. Recent evidence indicates that nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels activated by ACh and nicotine, may contribute to ethanol-mediated activation of VTA DAergic neurons although the nAChR subtype(s) involved has not been fully elucidated. Here we show that expression and activation of nAChRs containing the α6 subunit contribute to ethanol-induced activation of VTA DAergic neurons. In wild-type (WT) mouse midbrain sections that contain the VTA, ethanol (50 or 100 mM) significantly increased firing frequency of DAergic neurons. In contrast, ethanol did not significantly increase activity of VTA DAergic neurons in mice that do not express CHRNA6, the gene encoding the α6 nAChR subunit (α6 knock-out (KO) mice). Ethanol-induced activity in WT slices was also reduced by pre-application of the α6 subtype-selective nAChR antagonist, α-conotoxin MII[E11A]. When co-applied, ethanol potentiated the response to ACh in WT DAergic neurons; whereas co-application of ACh and ethanol failed to significantly increase activity of DAergic neurons in α6 KO slices. Finally, pre-application of α-conotoxin MII[E11A] in WT slices reduced ethanol potentiation of ACh responses. Together our data indicate that α6-subunit containing nAChRs may contribute to ethanol activation of VTA DAergic neurons. These receptors are predominantly expressed in DAergic neurons and known to be critical for nicotine reinforcement, providing a potential common therapeutic molecular target to reduce nicotine and alcohol co-abuse. PMID:23811312

  18. Gephyrin Cleavage in In Vitro Brain Ischemia Decreases GABAA Receptor Clustering and Contributes to Neuronal Death.

    PubMed

    Costa, João T; Mele, Miranda; Baptista, Márcio S; Gomes, João R; Ruscher, Karsten; Nobre, Rui J; de Almeida, Luís Pereira; Wieloch, Tadeusz; Duarte, Carlos B

    2016-08-01

    GABA (γ-aminobutyric acid) is the major inhibitory neurotransmitter in the central nervous system, and changes in GABAergic neurotransmission modulate the activity of neuronal networks. Gephyrin is a scaffold protein responsible for the traffic and synaptic anchoring of GABAA receptors (GABAAR); therefore, changes in gephyrin expression and oligomerization may affect the activity of GABAergic synapses. In this work, we investigated the changes in gephyrin protein levels during brain ischemia and in excitotoxic conditions, which may affect synaptic clustering of GABAAR. We found that gephyrin is cleaved by calpains following excitotoxic stimulation of hippocampal neurons with glutamate, as well as after intrahippocampal injection of kainate, giving rise to a stable cleavage product. Gephyrin cleavage was also observed in cultured hippocampal neurons subjected to transient oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia, and after transient middle cerebral artery occlusion (MCAO) in mice, a model of focal brain ischemia. Furthermore, a truncated form of gephyrin decreased the synaptic clustering of the protein, reduced the synaptic pool of GABAAR containing γ2 subunits and upregulated OGD-induced cell death in hippocampal cultures. Our results show that excitotoxicity and brain ischemia downregulate full-length gephyrin with a concomitant generation of truncated products, which affect synaptic clustering of GABAAR and cell death. PMID:26093381

  19. Sensitivity in detecting facial displays of emotion: Impact of maternal depression and oxytocin receptor genotype.

    PubMed

    Burkhouse, Katie L; Woody, Mary L; Owens, Max; McGeary, John E; Knopik, Valerie S; Gibb, Brandon E

    2016-01-01

    The current study examined sensitivity in detecting emotional faces among children of depressed and non-depressed mothers. A second goal was to examine the potential moderating role of the oxytocin receptor gene (OXTR rs53576), which has been linked to emotion recognition in the past. Participants included 247 children (ages 8-14). Children completed a forced choice emotion identification task. Maternal history of major depressive disorder during children's lives was associated with children's sensitivity in detecting emotional faces among children homozygous for the OXTR rs53576 G allele, but not among carriers of the A allele. Among G homozygotes, children of depressed mothers exhibited increased sensitivity in detecting sad faces, and reduced sensitivity in detecting happiness, compared to children of non-depressed mothers. PMID:25622005

  20. Associations between oxytocin receptor genotypes and social cognitive performance in individuals with schizophrenia.

    PubMed

    Davis, Michael C; Horan, William P; Nurmi, Erika L; Rizzo, Shemra; Li, Wendy; Sugar, Catherine A; Green, Michael F

    2014-11-01

    Individuals with schizophrenia often show substantial deficits in social cognitive abilities, which are strongly associated with social functioning. To advance our understanding of the genetic variation that is associated with social cognitive deficits in schizophrenia, we genotyped 74 schizophrenia outpatients who completed social cognitive performance measures assessing mentalizing, social perception, and emotional intelligence, as well as clinical symptoms. We assessed seven single nucleotide polymorphisms (SNPs) of the oxytocin receptor (OXTR) previously found to show replicable associations with socio-emotional processes. For one of the seven SNPs, rs2268493, the 'T' allele was significantly associated with poorer performance on a composite social cognition index, as well as specific tests of mentalizing and social perception. None of the SNPs were associated with clinical symptoms. Though the sample size is small, these findings provide initial support for the involvement of genetic variants of the OXTR in social cognitive impairments in schizophrenia. PMID:25244972

  1. Contribution of Estrone Sulfate to Cell Proliferation in Aromatase Inhibitor (AI) -Resistant, Hormone Receptor-Positive Breast Cancer

    PubMed Central

    Hanamura, Toru; Gohno, Tatsuyuki; Niwa, Toshifumi; Yamaguchi, Yuri; Horiguchi, Jun; Hayashi, Shin-ichi

    2016-01-01

    Aromatase inhibitors (AIs) effectively treat hormone receptor-positive postmenopausal breast cancer, but some patients do not respond to treatment or experience recurrence. Mechanisms of AI resistance include ligand-independent activation of the estrogen receptor (ER) and signaling via other growth factor receptors; however, these do not account for all forms of resistance. Here we present an alternative mechanism of AI resistance. We ectopically expressed aromatase in MCF-7 cells expressing green fluorescent protein as an index of ER activity. Aromatase-overexpressing MCF-7 cells were cultured in estrogen-depleted medium supplemented with testosterone and the AI, letrozole, to establish letrozole-resistant (LR) cell lines. Compared with parental cells, LR cells had higher mRNA levels of steroid sulfatase (STS), which converts estrone sulfate (E1S) to estrone, and the organic anion transporter peptides (OATPs), which mediate the uptake of E1S into cells. LR cells proliferated more in E1S-supplemented medium than did parental cells, and LR proliferation was effectively inhibited by an STS inhibitor in combination with letrozole and by ER-targeting drugs. Analysis of ER-positive primary breast cancer tissues showed a significant correlation between the increases in the mRNA levels of STS and the OATPs in the LR cell lines, which supports the validity of this AI-resistant model. This is the first study to demonstrate the contribution of STS and OATPs in E1S metabolism to the proliferation of AI-resistant breast cancer cells. We suggest that E1S metabolism represents a new target in AI-resistant breast cancer treatment. PMID:27228187

  2. The Natural Cytotoxicity Receptor 1 Contribution to Early Clearance of Streptococcus pneumoniae and to Natural Killer-Macrophage Cross Talk

    PubMed Central

    Yossef, Rami; Hadad, Uzi; Elkabets, Moshe; Vallon-Eberhard, Alexandra; Hulihel, Luai; Jung, Steffen; Ghadially, Hormas; Braiman, Alex; Apte, Ron N.; Mandelboim, Ofer; Dagan, Ron; Mizrachi-Nebenzahl, Yaffa; Porgador, Angel

    2011-01-01

    Natural killer (NK) cells serve as a crucial first line of defense against tumors, viral and bacterial infections. We studied the involvement of a principal activating natural killer cell receptor, natural cytotoxicity receptor 1 (NCR1), in the innate immune response to S. pneumoniae infection. Our results demonstrate that the presence of the NCR1 receptor is imperative for the early clearance of S. pneumoniae. We tied the ends in vivo by showing that deficiency in NCR1 resulted in reduced lung NK cell activation and lung IFNγ production at the early stages of S. pneumoniae infection. NCR1 did not mediate direct recognition of S. pneumoniae. Therefore, we studied the involvement of lung macrophages and dendritic cells (DC) as the mediators of NK-expressed NCR1 involvement in response to S. pneumoniae. In vitro, wild type BM-derived macrophages and DC expressed ligands to NCR1 and co-incubation of S. pneumoniae-infected macrophages/DC with NCR1-deficient NK cells resulted in significantly lesser IFNγ levels compared to NCR1-expressing NK cells. In vivo, ablation of lung macrophages and DC was detrimental to the early clearance of S. pneumoniae. NCR1-expressing mice had more potent alveolar macrophages as compared to NCR1-deficient mice. This result correlated with the higher fraction of NCR1-ligandhigh lung macrophages, in NCR1-expressing mice, that had better phagocytic activity compared to NCR1-liganddull macrophages. Overall, our results point to the essential contribution of NK-expressed NCR1 in early response to S. pneumoniae infection and to NCR1-mediated interaction of NK and S. pneumoniae infected-macrophages and -DC. PMID:21887255

  3. Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis.

    PubMed

    Washburn, Neal; Borgquist, Amanda; Wang, Kate; Jeffery, Garrett S; Kelly, Martin J; Wagner, Edward J

    2013-01-01

    We examined the receptor subtypes and signal transduction mechanisms contributing to the estrogenic modulation of cannabinoid-induced changes in energy balance. Food intake and, in some cases, O2 consumption, CO2 production and the respiratory exchange ratio were evaluated in ovariectomized female guinea pigs treated s.c. with the cannabinoid receptor agonist WIN 55,212-2 or its cremephor/ethanol/0.9% saline vehicle, and either with estradiol benzoate (EB), the estrogen receptor (ER) α agonist PPT, the ERβ agonist DPN, the Gq-coupled membrane ER agonist STX, the GPR30 agonist G-1 or their respective vehicles. Patch-clamp recordings were performed in hypothalamic slices. EB, STX, PPT and G-1 decreased daily food intake. Of these, EB, STX and PPT blocked the WIN 55,212-2-induced increase in food intake within 1-4 h. The estrogenic diminution of cannabinoid-induced hyperphagia correlated with a rapid (within 15 min) attenuation of cannabinoid-mediated decreases in glutamatergic synaptic input onto arcuate neurons, which was completely blocked by inhibition of protein kinase C (PKC) and attenuated by inhibition of protein kinase A (PKA). STX, but not PPT, mimicked this rapid estrogenic effect. However, PPT abolished the cannabinoid-induced inhibition of glutamatergic neurotransmission in cells from animals treated 24 h prior. The estrogenic antagonism of this presynaptic inhibition was observed in anorexigenic proopiomelanocortin neurons. These data reveal that estrogens negatively modulate cannabinoid-induced changes in energy balance via Gq-coupled membrane ER- and ERα-mediated mechanisms involving activation of PKC and PKA. As such, they further our understanding of the pathways through which estrogens act to temper cannabinoid sensitivity in regulating energy homeostasis in females. PMID:22538462

  4. ZFP521 contributes to pre-B-cell lymphomagenesis through modulation of the pre-B-cell receptor signaling pathway.

    PubMed

    Hiratsuka, T; Takei, Y; Ohmori, R; Imai, Y; Ozeki, M; Tamaki, K; Haga, H; Nakamura, T; Tsuruyama, T

    2016-06-23

    ZFP521 was previously identified as a putative gene involved in induction of B-cell lymphomagenesis. However, the contribution of ZFP521 to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521 in B-cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521 was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTK and BANK1 were positively regulated by the ZFP521 gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-myc and c-jun were upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-myc and c-jun and of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTK and BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521 in humans, was upregulated. In conclusion, our data showed that the ZFP521 gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway. PMID:26522721

  5. VOC emissions, evolutions and contributions to SOA formation at a receptor site in eastern China

    NASA Astrophysics Data System (ADS)

    Yuan, B.; Hu, W. W.; Shao, M.; Wang, M.; Chen, W. T.; Lu, S. H.; Zeng, L. M.; Hu, M.

    2013-09-01

    Volatile organic compounds (VOCs) were measured by two online instruments (GC-FID/MS and PTR-MS) at a receptor site on Changdao Island (37.99° N, 120.70° E) in eastern China. Reaction with OH radical dominated chemical losses of most VOC species during the Changdao campaign. A photochemical-age-based parameterization method is used to calculate VOC emission ratios and to quantify the evolution of ambient VOCs. The calculated emission ratios of most hydrocarbons agree well with those obtained from emission inventory data, but determined emission ratios of oxygenated VOCs (OVOCs) are significantly higher than those from emission inventory data. The photochemical-age-based parameterization method is also used to investigate primary emissions and secondary formation of organic aerosol. The primary emission ratio of organic aerosol (OA) to CO is determined to be 14.9 μg m-3 ppm-1, and secondary organic aeorosols (SOA) are produced at an enhancement ratio of 18.8 μg m-3 ppm-1 to CO after 50 h of photochemical processing in the atmosphere. SOA formation is significantly higher than the level determined from VOC oxidation under both high-NOx (2.0 μg m-3 ppm-1 CO) and low-NOx conditions (6.5 μg m-3 ppm-1 CO). Polycyclic aromatic hydrocarbons (PAHs) and higher alkanes (> C10) account for as high as 17.4% of SOA formation, which suggests semi-volatile organic compounds (SVOCs) may be a large contributor to SOA formation during the Changdao campaign. The SOA formation potential of primary VOC emissions determined from field campaigns in Beijing and Pearl River Delta (PRD) is lower than the measured SOA levels reported in the two regions, indicating SOA formation is also beyond explainable by VOC oxidation in the two city clusters.

  6. Activation of mitochondrial transient receptor potential vanilloid 1 channel contributes to microglial migration.

    PubMed

    Miyake, Takahito; Shirakawa, Hisashi; Nakagawa, Takayuki; Kaneko, Shuji

    2015-10-01

    Microglia, the resident immune cells in the brain, survey the environment of the healthy brain. Microglial migration is essential for many physiological and pathophysiological processes. Although microglia express some members of the transient receptor potential (TRP) channel family, there is little knowledge regarding the physiological roles of TRP channels in microglia. Here, we explored the role of TRP vanilloid 1 (TRPV1), a channel opened by capsaicin, heat, protons, and endovanilloids, in microglia. We found that application of capsaicin induced concentration-dependent migration in microglia derived from wild-type mice but not in those derived from TRPV1 knockout (TRPV1-KO) mice. Capsaicin-induced microglial migration was significantly inhibited by co-application of the TRPV1 blocker SB366791 and the Ca(2+) chelator BAPTA-AM. Using RT-PCR and immunocytochemistry, we validated that TRPV1 was expressed in microglia. Electrophysiological recording, intracellular Ca(2+) imaging, and immunocytochemistry indicated that TRPV1 was localized primarily in intracellular organelles. Treatment with capsaicin induced an increase in intramitochondrial Ca(2+) concentrations and mitochondrial depolarization. Furthermore, microglia derived from TRPV1-KO mice showed delayed Ca(2+) efflux compared with microglia derived from wild-type mice. Capsaicin-induced microglial migration was inhibited by membrane-permeable antioxidants and MAPK inhibitors, suggesting that mitochondrial TRPV1 activation induced Ca(2+) -dependent production of ROS followed by MAPK activation, which correlated with an augmented migration of microglia. Moreover, a mixture of three endovanilloids augmented microglial migration via TRPV1 activation. Together, these results indicate that mitochondrial TRPV1 plays an important role in inducing microglial migration. Activation of TRPV1 triggers an increase in intramitochondrial Ca(2+) concentration and following depolarization of mitochondria, which results in mt

  7. Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia

    PubMed Central

    Lee-Sherick, A B; Eisenman, K M; Sather, S; McGranahan, A; Armistead, P M; McGary, C S; Hunsucker, S A; Schlegel, J; Martinson, H; Cannon, C; Keating, A K; Earp, H S; Liang, X; DeRyckere, D; Graham, D K

    2013-01-01

    Acute myeloid leukemia (AML) continues to be extremely difficult to treat successfully, and the unacceptably low overall survival rates mandate that we assess new potential therapies to ameliorate poor clinical response to conventional therapy. Abnormal tyrosine kinase activation in AML has been associated with poor prognosis and provides strategic targets for novel therapy development. We found that Mer receptor tyrosine kinase was over-expressed in a majority of pediatric (29/36, 80%) and adult (10/10, 100%) primary AML patient blasts at the time of diagnosis, and 100% of patient samples at the time of relapse. Mer was also found to be expressed in 12 of 14 AML cell lines (86%). In contrast, normal bone marrow myeloid precursors expressed little to no Mer. Following AML cell line stimulation with Gas6, a Mer ligand, we observed activation of prosurvival and proliferative signaling pathways, including phosphorylation of ERK1/2, p38, MSK1, CREB, ATF1, AKT and STAT6. To assess the phenotypic role of Mer in AML, two independent short-hairpin RNA (shRNA) constructs were used to decrease Mer expression in the AML cell lines Nomo-1 and Kasumi-1. Reduction of Mer protein levels significantly increased rates of myeloblast apoptosis two to threefold in response to serum starvation. Furthermore, myeloblasts with knocked-down Mer demonstrated decreased colony formation by 67–87%, relative to control cell lines (P<0.01). NOD-SCID-gamma mice transplanted with Nomo-1 myeloblasts with reduced levels of Mer had a significant prolongation in survival compared with mice transplanted with the parental or control cell lines (median survival 17 days in parental and control cell lines, versus 32–36 days in Mer knockdown cell lines, P<0.0001). These data suggest a role for Mer in acute myeloid leukemogenesis and indicate that targeted inhibition of Mer may be an effective therapeutic strategy in pediatric and adult AML. PMID:23474756

  8. Aberrant Mer receptor tyrosine kinase expression contributes to leukemogenesis in acute myeloid leukemia.

    PubMed

    Lee-Sherick, A B; Eisenman, K M; Sather, S; McGranahan, A; Armistead, P M; McGary, C S; Hunsucker, S A; Schlegel, J; Martinson, H; Cannon, C; Keating, A K; Earp, H S; Liang, X; DeRyckere, D; Graham, D K

    2013-11-14

    Acute myeloid leukemia (AML) continues to be extremely difficult to treat successfully, and the unacceptably low overall survival rates mandate that we assess new potential therapies to ameliorate poor clinical response to conventional therapy. Abnormal tyrosine kinase activation in AML has been associated with poor prognosis and provides strategic targets for novel therapy development. We found that Mer receptor tyrosine kinase was over-expressed in a majority of pediatric (29/36, 80%) and adult (10/10, 100%) primary AML patient blasts at the time of diagnosis, and 100% of patient samples at the time of relapse. Mer was also found to be expressed in 12 of 14 AML cell lines (86%). In contrast, normal bone marrow myeloid precursors expressed little to no Mer. Following AML cell line stimulation with Gas6, a Mer ligand, we observed activation of prosurvival and proliferative signaling pathways, including phosphorylation of ERK1/2, p38, MSK1, CREB, ATF1, AKT and STAT6. To assess the phenotypic role of Mer in AML, two independent short-hairpin RNA (shRNA) constructs were used to decrease Mer expression in the AML cell lines Nomo-1 and Kasumi-1. Reduction of Mer protein levels significantly increased rates of myeloblast apoptosis two to threefold in response to serum starvation. Furthermore, myeloblasts with knocked-down Mer demonstrated decreased colony formation by 67-87%, relative to control cell lines (P<0.01). NOD-SCID-gamma mice transplanted with Nomo-1 myeloblasts with reduced levels of Mer had a significant prolongation in survival compared with mice transplanted with the parental or control cell lines (median survival 17 days in parental and control cell lines, versus 32-36 days in Mer knockdown cell lines, P<0.0001). These data suggest a role for Mer in acute myeloid leukemogenesis and indicate that targeted inhibition of Mer may be an effective therapeutic strategy in pediatric and adult AML. PMID:23474756

  9. Overexpression of protease-activated receptor-1 contributes to melanoma metastasis via regulation of connexin 43.

    PubMed

    Villares, Gabriel J; Dobroff, Andrey S; Wang, Hua; Zigler, Maya; Melnikova, Vladislava O; Huang, Li; Bar-Eli, Menashe

    2009-08-15

    Protease-activated receptor-1 (PAR-1) is a key player in melanoma metastasis with higher expression seen in metastatic melanoma cell lines and tissue specimens. cDNA microarray and Western blot analyses reveal that the gap junctional intracellular communication molecule connexin 43 (Cx-43), known to be involved in tumor cell diapedesis and attachment to endothelial cells, is significantly decreased after PAR-1 silencing in metastatic melanoma cell lines. Furthermore, Cx-43 promoter activity was significantly inhibited in PAR-1-silenced cells, suggesting that PAR-1 regulates Cx-43 at the transcriptional level. Chromatin immunoprecipitation studies showed a reduction in the binding of SP-1 and AP-1 transcription factors to the promoter of Cx-43. Both transcription factors have been shown previously to be required for maximal Cx-43 promoter activity. These results were corroborated by mutating the AP-1 and SP-1 binding sites resulting in decreased Cx-43 promoter activity in PAR-1-positive cells. Moreover, as Cx-43 has been shown to facilitate arrest of circulating tumor cells at the vascular endothelium, melanoma cell attachment to endothelial cells was significantly decreased in PAR-1-silenced cells, with this effect being abrogated after PAR-1 rescue. Herein, we report that up-regulation of PAR-1 expression, seen in melanoma progression, mediates high levels of Cx-43 expression. As both SP-1 and AP-1 transcription factors act as positive regulators of Cx-43, our data provide a novel mechanism for the regulation of Cx-43 expression by PAR-1. Indeed, Cx-43 expression was restored following PAR-1 rescue in PAR-1-silenced cells. Taken together, our data support the tumor promoting function of Cx-43 in melanoma. PMID:19679555

  10. Overexpression of Protease Activated Receptor-1 Contributes to Melanoma Metastasis via Regulation of Connexin 43

    PubMed Central

    Villares, Gabriel J.; Dobroff, Andrey S.; Wang, Hua; Zigler, Maya; Melnikova, Vladislava O.; Huang, Li; Bar-Eli, Menashe

    2009-01-01

    Protease Activated Receptor-1 (PAR-1) is a key player in melanoma metastasis with higher expression seen in metastatic melanoma cell lines and tissue specimens. cDNA microarray and Western blot analyses reveal that the gap junctional intracellular communication molecule, Connexin 43 (Cx-43), known to be involved in tumor cell diapedesis and attachment to endothelial cells, is significantly decreased after PAR-1 silencing in metastatic melanoma cell lines. Furthermore, Cx-43 promoter activity was significantly inhibited in PAR-1 silenced cells suggesting that PAR-1 regulates Cx-43 at the transcriptional level. Chromatin Immunoprecipitation studies found a reduction in the binding of SP-1 and AP-1 transcription factors to the promoter of Cx-43. Both transcription factors have previously been shown to be required for maximal Cx-43 promoter activity. These results were corroborated by mutating the AP-1 and SP-1 binding sites resulting in decreased Cx-43 promoter activity in PAR-1 positive cells. Moreover, as Cx-43 has been shown to facilitate arrest of circulating tumor cells at the vascular endothelium, melanoma cell attachment to endothelial cells was significantly decreased in PAR-1 silenced cells with this effect being abrogated after PAR-1 rescue. Herein, we report that upregulation of PAR-1 expression seen in melanoma progression, mediates high levels of Cx-43 expression. As both SP-1 and AP-1 transcription factors act as positive regulators of Cx-43, our data provide a novel mechanism for the regulation of Cx-43 expression by PAR-1. Indeed, Cx-43 expression was restored following PAR-1 rescue in PAR-1 silenced cells. Taken together, our data support the tumor promoting function of Connexin 43 in melanoma. PMID:19679555

  11. The aryl hydrocarbon receptor: differential contribution to T helper 17 and T cytotoxic 17 cell development.

    PubMed

    Hayes, Mark D; Ovcinnikovs, Vitalijs; Smith, Andrew G; Kimber, Ian; Dearman, Rebecca J

    2014-01-01

    The aryl hydrocarbon receptor (AhR) has been shown to be required for optimal Thelper (Th) 17 cell activation. Th17 cells provide immunity against extracellular pathogens and are implicated in autoimmune diseases. Herein, the role of the AhR in cytokine production by Th17, and by the analogous population of T cytotoxic (Tc)17 cells, has been examined. Lymph node Tc (CD8(+)) and Th (CD4(+)) cells were isolated by negative selection from naive AhR(+/-) and AhR(-/-) mice and polarised to Tc1/Th1 or Tc17/Th17 phenotypes with appropriate cytokines. Cell differentiation was assessed as a function of mRNA and protein (ELISA and flow cytometry) expression for interferon (IFN)-γ and for key Th17 cytokines. In AhR(+/-) mice, Th17 cells displayed an exclusive IL-17 profile, which was markedly inhibited by a selective AhR antagonist to levels observed in AhR knockout mice. Addition of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) markedly enhanced Th17 cell activity in the heterozygotes. In contrast, Tc17 cells polarised into 3 distinct subsets: producing either IL-17 or IFN-γ alone, or both cytokines. Blocking AhR was also detrimental to Tc17 development, with reduced responses recorded in AhR(-/-) mice and antagonist-mediated reduction of IL-17 expression in the heterozygotes. However, Tc17 cells were largely refractory to exogenous FICZ, presumably because Tc17 cells express baseline AhR mRNA, but unlike Th17 cells, there is no marked up-regulation during polarisation. Thus, Th17 cell development is more dependent upon AhR activation than is Tc17 cell development, suggesting that endogenous AhR ligands play a much greater role in driving Th17 cell responses. PMID:25203682

  12. NMDA and AMPA receptors contribute similarly to temporal processing in mammalian retinal ganglion cells

    PubMed Central

    Stafford, Benjamin K; Manookin, Michael B; Singer, Joshua H; Demb, Jonathan B

    2014-01-01

    Postsynaptic AMPA- and NMDA-type glutamate receptors (AMPARs, NMDARs) are commonly expressed at the same synapses. AMPARs are thought to mediate the majority of fast excitatory neurotransmission whereas NMDARs, with their relatively slower kinetics and higher Ca2+ permeability, are thought to mediate synaptic plasticity, especially in neural circuits devoted to learning and memory. In sensory neurons, however, the roles of AMPARs and NMDARs are less well understood. Here, we tested in the in vitro guinea pig retina whether AMPARs and NMDARs differentially support temporal contrast encoding by two ganglion cell types. In both OFF Alpha and Delta ganglion cells, contrast stimulation evoked an NMDAR-mediated response with a characteristic J-shaped I–V relationship. In OFF Delta cells, AMPAR- and NMDAR-mediated responses could be modulated at low frequencies but were suppressed during 10 Hz stimulation, when responses were instead shaped by synaptic inhibition. With inhibition blocked, both AMPAR- and NMDAR-mediated responses could be modulated at 10 Hz, indicating that NMDAR kinetics do not limit temporal encoding. In OFF Alpha cells, NMDAR-mediated responses followed stimuli at frequencies up to ∼18 Hz. In both cell types, NMDAR-mediated responses to contrast modulation at 9–18 Hz showed delays of <10 ms relative to AMPAR-mediated responses. Thus, NMDARs combine with AMPARs to encode rapidly modulated glutamate release, and NMDAR kinetics do not limit temporal coding by OFF Alpha and Delta ganglion cells substantially. Furthermore, glutamatergic transmission is differentially regulated across bipolar cell pathways: in some, release is suppressed at high temporal frequencies by presynaptic inhibition. PMID:25217374

  13. Neuropeptide S receptor gene variant and environment: contribution to alcohol use disorders and alcohol consumption.

    PubMed

    Laas, Kariina; Reif, Andreas; Akkermann, Kirsti; Kiive, Evelyn; Domschke, Katharina; Lesch, Klaus-Peter; Veidebaum, Toomas; Harro, Jaanus

    2015-05-01

    The functional polymorphism Asn(107) Ile (rs324981, A > T) of the neuropeptide S receptor (NPSR1) gene is involved in the modulation of traits that affect alcohol use. Hence, we have examined whether the NPSR1 A/T polymorphism is associated with alcohol use disorders (AUD) and alcohol use in a population-representative sample. Lifetime AUD were assessed by the MINI psychiatric interview (n = 501) in the older cohort of the longitudinal Estonian Children Personality Behaviour and Health Study at age 25. Alcohol use, environmental adversities and personality were reported by both the younger (original n = 583) and the older cohort (original n = 593) in three study waves. NPSR1 associations with AUD and alcohol use differed by sex. In females, both AUD [odds ratio (OR) = 7.20 (0.94-55.0), P = 0.029] and harmful alcohol use were more prevalent in A-allele carriers. In contrast, in males, AUD was more frequent in T-allele carriers [OR = 2.75 (1.19-6.36), P = 0.017], especially if exposed to adverse environments at age 15 [OR = 10 (1.18-84.51), P = 0.019]. Alcohol use was higher in male T-allele carriers at ages 15 and 18 as well. Similarly to females, however, the risk allele for higher alcohol use for males at age 25 was the A-allele. Many of the effects on alcohol use were explained by genotype effects on measures of personality. In the general population, the NPSR1 Asn(107) Ile polymorphism is associated with AUD and alcohol consumption, dependent on sex, environment and age. The results are in line with the impulsivity and personality regulating role of the NPSR1. PMID:24754478

  14. The Aryl Hydrocarbon Receptor: Differential Contribution to T Helper 17 and T Cytotoxic 17 Cell Development

    PubMed Central

    Hayes, Mark D.; Ovcinnikovs, Vitalijs; Smith, Andrew G.; Kimber, Ian; Dearman, Rebecca J.

    2014-01-01

    The aryl hydrocarbon receptor (AhR) has been shown to be required for optimal Thelper (Th) 17 cell activation. Th17 cells provide immunity against extracellular pathogens and are implicated in autoimmune diseases. Herein, the role of the AhR in cytokine production by Th17, and by the analogous population of T cytotoxic (Tc)17 cells, has been examined. Lymph node Tc (CD8+) and Th (CD4+) cells were isolated by negative selection from naive AhR+/− and AhR−/− mice and polarised to Tc1/Th1 or Tc17/Th17 phenotypes with appropriate cytokines. Cell differentiation was assessed as a function of mRNA and protein (ELISA and flow cytometry) expression for interferon (IFN)-γ and for key Th17 cytokines. In AhR+/− mice, Th17 cells displayed an exclusive IL-17 profile, which was markedly inhibited by a selective AhR antagonist to levels observed in AhR knockout mice. Addition of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) markedly enhanced Th17 cell activity in the heterozygotes. In contrast, Tc17 cells polarised into 3 distinct subsets: producing either IL-17 or IFN-γ alone, or both cytokines. Blocking AhR was also detrimental to Tc17 development, with reduced responses recorded in AhR−/− mice and antagonist-mediated reduction of IL-17 expression in the heterozygotes. However, Tc17 cells were largely refractory to exogenous FICZ, presumably because Tc17 cells express baseline AhR mRNA, but unlike Th17 cells, there is no marked up-regulation during polarisation. Thus, Th17 cell development is more dependent upon AhR activation than is Tc17 cell development, suggesting that endogenous AhR ligands play a much greater role in driving Th17 cell responses. PMID:25203682

  15. Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction.

    PubMed

    Gueret, Alexandre; Harouki, Najah; Favre, Julie; Galmiche, Guillaume; Nicol, Lionel; Henry, Jean-Paul; Besnier, Marie; Thuillez, Christian; Richard, Vincent; Kolkhof, Peter; Mulder, Paul; Jaisser, Frédéric; Ouvrard-Pascaud, Antoine

    2016-04-01

    Mineralocorticoid receptor (MR) antagonists slow down the progression of heart failure after myocardial infarction (MI), but the cell-specific role of MR in these benefits is unclear. In this study, the role of MR expressed in vascular smooth muscle cells (VSMCs) was investigated. Two months after coronary artery ligation causing MI, mice with VSMC-specific MR deletion (MI-MR(SMKO)) and mice treated with the MR antagonist finerenone (MI-fine) had improved left ventricular compliance and elastance when compared with infarcted control mice (MI-CTL), as well as reduced interstitial fibrosis. Importantly, the coronary reserve assessed by magnetic resonance imaging was preserved (difference in myocardial perfusion before and after induction of vasodilatation, mL mg (-1) min(-1): MI-CTL: 1.1±0.5, nonsignificant; MI-MR(SMKO): 4.6±1.6 [P<0.05]; MI-fine: 3.6±0.7 [P<0.01]). The endothelial function, tested on isolated septal coronary arteries by analyzing the acetylcholine-induced nitric oxide-dependent relaxation, was also improved by MR deletion in VSMCs or by finerenone treatment (relaxation %: MI-CTL: 36±5, MI-MR(SMKO): 54±3, and MI-fine: 76±4; P<0.05). Such impairment of the coronary endothelial function on MI involved an oxidative stress that was reduced when MR was deleted in VSMCs or by finerenone treatment. Moreover, short-term incubation of coronary arteries isolated from noninfarcted animals with low-dose angiotensin-II (10(-9) mol/L) induced oxidative stress and impaired acetylcholine-induced relaxation in CTL but neither in MR(SMKO) nor in mice pretreated with finerenone. In conclusion, deletion of MR in VSMCs improved left ventricular dysfunction after MI, likely through maintenance of the coronary reserve and improvement of coronary endothelial function. MR blockage by finerenone had similar effects. PMID:26902493

  16. The contribution of IL-6 to beta 3 adrenergic receptor mediated adipose tissue remodeling.

    PubMed

    Buzelle, Samyra L; MacPherson, Rebecca E K; Peppler, Willem T; Castellani, Laura; Wright, David C

    2015-02-01

    The chronic activation of beta 3 adrenergic receptors results in marked alterations in adipose tissue morphology and metabolism, including increases in mitochondrial content and the expression of enzymes involved in lipogenesis and glyceroneogenesis. Acute treatment with CL 316,243, a beta 3 adrenergic agonist, induces the expression of interleukin 6. Interestingly, IL-6 has been shown to induce mitochondrial genes in cultured adipocytes. Therefore, the purpose of this paper was to examine the role of interleukin 6 in mediating the in vivo effects of CL 316,243 in white adipose tissue. Circulating IL-6, and markers of IL-6 signaling in white adipose tissue were increased 4 h following a single injection of CL 316,243 in C57BL6/J mice. Once daily injections of CL 316,243 for 5 days increased the protein content of a number of mitochondrial proteins including CORE1, Cytochrome C, PDH, MCAD, and Citrate Synthase to a similar extent in adipose tissue from WT and IL-6(-/-) mice. Conversely, CL 316,243-induced increases in COXIV and phosphorylated AMPK were attenuated in IL-6(-/-) mice. Likewise, the slight, but significant, CL 316,243-induced increases in ATGL, PEPCK, and PPARγ, were reduced or absent in adipose tissue IL-6(-/-) mice. The attenuated response to CL 316,243 in white adipose tissue in IL-6(-/-) mice was associated with reductions in whole-body oxygen consumption and energy expenditure in the light phase. Our findings suggest that IL-6 plays a limited role in CL 316,243-mediated adipose tissue remodeling. PMID:25713332

  17. The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

    PubMed Central

    Trinath, Jamma; Holla, Sahana; Mahadik, Kasturi; Prakhar, Praveen; Singh, Vikas

    2014-01-01

    Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of β-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1β, and tumor necrosis factor alpha (TNF-α). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host. PMID:25246634

  18. The WNT signaling pathway contributes to dectin-1-dependent inhibition of Toll-like receptor-induced inflammatory signature.

    PubMed

    Trinath, Jamma; Holla, Sahana; Mahadik, Kasturi; Prakhar, Praveen; Singh, Vikas; Balaji, Kithiganahalli Narayanaswamy

    2014-12-01

    Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of β-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1β, and tumor necrosis factor alpha (TNF-α). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host. PMID:25246634

  19. Parsing ERK Activation Reveals Quantitatively Equivalent Contributions From Epidermal Growth Factor Receptor and HER2 In Human Mammary Epithelial Cells

    SciTech Connect

    Hendriks, Bart S.; Orr, Galya; Wells, Alan H.; Wiley, H. S.; Lauffenburger, Douglas A.

    2005-02-18

    HER2, a member of the EGFR tyrosine kinase family, functions as an accessory EGFR signaling component and alters EGFR trafficking by heterodimerization. HER2 overexpression leads to aberrant cell behavior including enhanced proliferation and motility. Here we apply a combination of computational modeling and quantitative experimental studies of the dynamic interactions between EGFR and HER2, and their downstream activation of extracellular signal-related kinase (ERK) to understand this complex signaling system. Using cells expressing different levels of HER2 relative to the EGFR, we can separate relative contributions of EGFR and HER2 to signaling amplitude and duration. Based on our model calculations, we demonstrate that, in contrast with previous suggestions in the literature, the intrinsic capabilities of EGFR and HER2 to activated ERK are quantitatively equivalent . We find that HER2-mediated effects on EGFR dimerization and trafficking are sufficient to explain the detected HER2-mediated amplification of EGF-induced ERK signaling. Our model suggests that transient amplification of ERK activity by HER2 arises predominantly from the 2-to-1 stoichiometry of receptor kinase to bound ligand in EGFR/HER2 heterodimers compared to the 1-to-1 stoichiometry of the EGFR homodimer, but alterations in receptor trafficking, with resultant EGFR sparing, cause the sustained HER2-mediated enhancement of ERK signaling.

  20. Bioassays for TSH Receptor Autoantibodies, from FRTL-5 Cells to TSH Receptor–LH/CG Receptor Chimeras: The Contribution of Leonard D. Kohn

    PubMed Central

    Giuliani, Cesidio; Saji, Motoyasu; Bucci, Ines; Napolitano, Giorgio

    2016-01-01

    Since the discovery 60 years ago of the “long-acting thyroid stimulator” by Adams and Purves, great progress has been made in the detection of thyroid-stimulating hormone (TSH) receptor (TSHR) autoantibodies (TRAbs) in Graves’ disease. Today, commercial assays are available that can detect TRAbs with high accuracy and provide diagnostic and prognostic evaluation of patients with Graves’ disease. The present review focuses on the development of TRAbs bioassays, and particularly on the role that Leonard D. Kohn had in this. Indeed, 30 years ago, the Kohn group developed a bioassay based on the use of FRTL-5 cells that was characterized by high reproducibility, feasibility, and diagnostic accuracy. Using this FRTL-5 bioassay, Kohn and his colleagues were the first to develop monoclonal antibodies (moAbs) against the TSHR. Furthermore, they demonstrated the multifaceted functional nature of TRAbs in patients with Graves’ disease, with the identification of stimulating and blocking TRAbs, and even antibodies that activated pathways other than cAMP. After the cloning of the TSHR, the Kohn laboratory constructed human TSHR–rat luteinizing hormone/chorionic gonadotropin receptor chimeras. This paved the way to a new bioassay based on the use of non-thyroid cells transfected with the Mc4 chimera. The new Mc4 bioassay is characterized by high diagnostic and prognostic accuracy, greater than for other assays. The availability of a commercial kit based on the Mc4 chimera is spreading the use of this assay worldwide, indicating its benefits for these patients with Graves’ disease. This review also describes the main contributions made by other researchers in TSHR molecular biology and TRAbs assay, especially with the development of highly potent moAbs. A comparison of the diagnostic accuracies of the main TRAbs assays, as both immunoassays and bioassays, is also provided. PMID:27504107

  1. Tachykinin NK3 receptor contribution to systemic release of vasopressin and oxytocin in response to osmotic and hypotensive challenge.

    PubMed

    Haley, Gwendolen E; Flynn, Francis W

    2007-08-01

    Activation of the neurokinin 3 receptor (NK3R) by a receptor agonist, hypotension, and hyperosmolarity results in the internalization of NK3R expressed by magnocellular neurons and the release of vasopressin (VP) and oxytocin (OT) into the circulation. The contribution of NK3R activation to the release of VP and OT in response to hyperosmolarity and hypotension was evaluated by measuring the release of both hormones following pretreatment with a selective NK3R antagonist, SB-222200. Freely behaving male rats were given an intraventricular injection of either 0.15 M NaCl or 250, 500, or 1,000 pmol SB-222200, and then were administered an intravenous infusion of 2 M NaCl or 0.15 M NaCl (experiment 1), or a bolus intra injection of 0.15 M NaCl or hydralazine (HDZ), a hypotension-inducing drug (experiment 2). Blood samples were taken from indwelling arterial catheters at various time points for 1-2 h, both before and after treatments. Plasma VP and OT levels were determined by ELISA. Blockade of NK3R did not affect the baseline levels of either hormone. In contrast, pretreatment with SB-222200 significantly reduced ( approximately 60%) or abolished the release of VP and OT, respectively, to 2 M NaCl infusion. HDZ-induced VP and OT release was eliminated by pretreatment with 500 pmol SB-222200. Therefore, NK3R activation contributes significantly to the systemic release of both VP and OT in response to osmotic and hypotensive challenges. PMID:17522129

  2. Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.

    PubMed

    Orme, Jacob J; Du, Yong; Vanarsa, Kamala; Mayeux, Jessica; Li, Li; Mutwally, Azza; Arriens, Cristina; Min, Soyoun; Hutcheson, Jack; Davis, Laurie S; Chong, Benjamin F; Satterthwaite, Anne B; Wu, Tianfu; Mohan, Chandra

    2016-08-01

    Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE. PMID:27237127

  3. Biphasic modulation by mGlu5 receptors of TRPV1-mediated intracellular calcium elevation in sensory neurons contributes to heat sensitivity

    PubMed Central

    Masuoka, T; Nakamura, T; Kudo, M; Yoshida, J; Takaoka, Y; Kato, N; Ishibashi, T; Imaizumi, N; Nishio, M

    2015-01-01

    Background and Purpose Elevation of glutamate, an excitatory amino acid, during inflammation and injury plays a crucial role in the reception and transmission of sensory information via ionotropic and metabotropic receptors. This study aimed to investigate the mechanisms underlying the biphasic effects of metabotropic glutamate mGlu5 receptor activation on responses to noxious heat. Experimental Approach We assessed the effects of intraplantar quisqualate, a non-selective glutamate receptor agonist, on heat and mechanical pain behaviours in mice. In addition, the effects of quisqualate on the intracellular calcium response and on membrane currents mediated by TRPV1 channels, were examined in cultured dorsal root ganglion neurons from mice. Key Results Activation of mGlu5 receptors in hind paw transiently increased, then decreased, the response to noxious heat. In sensory neurons, activation of mGlu5 receptors potentiated TRPV1-mediated intracellular calcium elevation, while terminating activation of mGlu5 receptors depressed it. TRPV1-induced currents were potentiated by activation of mGlu5 receptors under voltage clamp conditions and these disappeared after washout. However, voltage-gated calcium currents were inhibited by the mGlu5 receptor agonist, even after washout. Conclusions and Implications These results suggest that, in sensory neurons, mGlu5 receptors biphasically modulate TRPV1-mediated intracellular calcium response via transient potentiation of TRPV1 channel-induced currents and persistent inhibition of voltage-gated calcium currents, contributing to heat hyper- and hypoalgesia. PMID:25297838

  4. Oxytocin receptor ligands induce changes in cytoskeleton in neuroblastoma cells.

    PubMed

    Bakos, Jan; Strbak, Vladimir; Paulikova, Helena; Krajnakova, Lucia; Lestanova, Zuzana; Bacova, Zuzana

    2013-07-01

    Aim of the present study was to evaluate effects of ligands of oxytocin receptors on gene expression of neurofilament proteins (nestin and microtubule-associated protein 2 (MAP2)) associated with neuronal differentiation and growth factors (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) related to neuronal growth. Fluorescent staining of F-actin was used to observe morphology of cells. Co-treatment with oxytocin and oxytocin receptor antagonist--atosiban--resulted in significant increase of MAP2 gene expression in SK-N-SH cells. There was no effect of oxytocin on gene expression of growth factors BDNF and NGF. Surprisingly, oxytocin with atosiban significantly increased mRNA levels for both BDNF and NGF. Gene expression of vasopressin receptor (V1aR) significantly decreased in response to vasopressin. Atosiban decreased mRNA levels for oxytocin receptor (OXTR) and V1aR. Oxytocin significantly decreased OXTR and nestin mRNA levels and increased mRNA levels for BDNF and NGF in U-87 MG cells. The densest recruitment of F-actin filaments was observed in apical parts of filopodia in SK-N-SH cells incubated in oxytocin presence. Present data demonstrate complex role of ligands of oxytocin receptors in regulation of gene expression of intermediate filaments and thus, oxytocin might be considered as a growth factor in neuronal type of cells. PMID:23335033

  5. VOC emissions, evolutions and contributions to SOA formation at a receptor site in Eastern China

    NASA Astrophysics Data System (ADS)

    Yuan, B.; Hu, W. W.; Shao, M.; Wang, M.; Chen, W. T.; Lu, S. H.; Zeng, L. M.; Hu, M.

    2013-03-01

    Volatile organic compounds (VOCs) were measured by two online instruments (GC-FID/MS and PTR-MS) at a receptor site on Changdao Island (37.99° N, 120.70° E) in eastern China. Reaction with OH radical dominated the chemical loss of most VOC species during the Changdao campaign. A photochemical age based parameterization method is used to calculate VOC emission ratios and to quantify the evolution of ambient VOCs. The calculated emission ratios of most hydrocarbons agree well with those obtained from emission inventory, but the emission ratios of oxygenated VOCs (OVOCs) are significantly lower than those from emission inventory. The photochemical age based parameterization method is also used to investigate primary emissions and secondary formation of organic aerosol. The primary emission ratio of OA to CO are determined to be 14.9 μg m-3 ppm-1 and SOA are produced at an enhancement ratio of 18.8 μg m-3 ppm-1 to CO after 50 h of photochemical processing in the atmosphere. SOA formation is significantly higher than the level determined from VOC oxidation under both high-NOx (2.0 μg m-3 ppm-1 CO) and low-NOx condition (6.5 μg m-3 ppm-1 CO). Polycyclic aromatic hydrocarbons (PAHs) and higher alkanes (>C10) account for as high as 17.4% of SOA formation, which suggests semi-volatile organic compounds (SVOCs) may be a large contributor to SOA formation during the Changdao campaign. SOA formation potential of primary VOC emissions determined from both field campaigns and emission inventory in China are lower than the measured SOA levels reported in Beijing and Pearl River Delta (PRD), indicating SOA formation cannot be explained by VOC oxidation in this regions. SOA budget in China is estimated to be 5.0-13.7 Tg yr-1, with a fraction of at least 2.7 Tg yr-1 from anthropogenic emissions, which are much higher than the previous estimates from regional models.

  6. New contributions to the study of common double mutants in the human LDL receptor gene

    NASA Astrophysics Data System (ADS)

    Tejedor, M. Teresa; Cenarro, Ana; Tejedor, Diego; Stef, Marianne; Palacios, Lourdes; de Castro, Isabel; García-Otín, Ángel L.; Monteagudo, Luis V.; Civeira, Fernando; Pocovi, Miguel

    2011-11-01

    Variations in the gene encoding the low-density lipoprotein receptor ( LDLR) can cause familial hypercholesterolemia (FH), one of the most common inherited metabolic disorders in humans. The functional effects of the p.Gln92Glu and p.Asn564His alterations are predicted as benign, but the c.313 + 1G>C and p.Lys799_Phe801del changes are believed to cause disease. Although p.Gln92Glu and c.313 + 1G>C have been observed only in Spain, p.Asn564His and p.Lys799_Phe801del are widespread in Western Europe. In order to estimate the ages ( t generations) of these four variants of the gene, to determine their possible origin and to consider the influence of age and selective pressure on their spread, we analyzed 86 healthy individuals and 126 FH patients in Spain. Most of the FH patients investigated carried two of these four LDLR variants simultaneously, while only one patient carried three of them simultaneously. Haplotype analyses were based on five LDLR SNPs: c.81T>C, c.1413G>A, c.1725C>T, c.1959T>C and c.2232G>A. The results suggest that p.Gln92Glu and c.313 + 1G>C arose at about the same time (99 and 103 generations ago, respectively) in the CACTG haplotype and that p.Asn564His and p.Lys799_Phe801del appeared in the CGCCG haplotype and might be slightly more recent variations (92 and 95 generations ago, respectively). Low selective pressures could explain the maintenance of these variants in spite of their ages. The origin of p.Gln92Glu and c.313 + 1G>C appears to be in Spain whereas p.Asn564His and p.Lys799_Phe801del could have been introduced in Spain by Celtic migrations in the seventh to fifth centuries BC.

  7. New contributions to the study of common double mutants in the human LDL receptor gene.

    PubMed

    Tejedor, M Teresa; Cenarro, Ana; Tejedor, Diego; Stef, Marianne; Palacios, Lourdes; de Castro, Isabel; García-Otín, Angel L; Monteagudo, Luis V; Civeira, Fernando; Pocovi, Miguel

    2011-11-01

    Variations in the gene encoding the low-density lipoprotein receptor (LDLR) can cause familial hypercholesterolemia (FH), one of the most common inherited metabolic disorders in humans. The functional effects of the p.Gln92Glu and p.Asn564His alterations are predicted as benign, but the c.313 + 1G>C and p.Lys799_Phe801del changes are believed to cause disease. Although p.Gln92Glu and c.313 + 1G>C have been observed only in Spain, p.Asn564His and p.Lys799_Phe801del are widespread in Western Europe. In order to estimate the ages (t generations) of these four variants of the gene, to determine their possible origin and to consider the influence of age and selective pressure on their spread, we analyzed 86 healthy individuals and 126 FH patients in Spain. Most of the FH patients investigated carried two of these four LDLR variants simultaneously, while only one patient carried three of them simultaneously. Haplotype analyses were based on five LDLR SNPs: c.81T>C, c.1413G>A, c.1725C>T, c.1959T>C and c.2232G>A. The results suggest that p.Gln92Glu and c.313 + 1G>C arose at about the same time (99 and 103 generations ago, respectively) in the CACTG haplotype and that p.Asn564His and p.Lys799_Phe801del appeared in the CGCCG haplotype and might be slightly more recent variations (92 and 95 generations ago, respectively). Low selective pressures could explain the maintenance of these variants in spite of their ages. The origin of p.Gln92Glu and c.313 + 1G>C appears to be in Spain whereas p.Asn564His and p.Lys799_Phe801del could have been introduced in Spain by Celtic migrations in the seventh to fifth centuries BC. PMID:21935675

  8. Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling

    PubMed Central

    Wen, Jiaming; Jiang, Xianzhen; Dai, Yingbo; Zhang, Yujin; Tang, Yuxin; Sun, Hong; Mi, Tiejuan; Phatarpekar, Prasad V.; Kellems, Rodney E.; Blackburn, Michael R.; Xia, Yang

    2010-01-01

    Priapism is a condition of persistent penile erection in the absence of sexual excitation. Of men with sickle cell disease (SCD), 40% display priapism. The disorder is a dangerous and urgent condition, given its association with penile fibrosis and eventual erectile dysfunction. Current strategies to prevent its progression are poor because of a lack of fundamental understanding of the molecular mechanisms for penile fibrosis in priapism. Here we demonstrate that increased adenosine is a novel causative factor contributing to penile fibrosis in two independent animal models of priapism, adenosine deaminase (ADA)-deficient mice and SCD transgenic mice. An important finding is that chronic reduction of adenosine by ADA enzyme therapy successfully attenuated penile fibrosis in both mouse models, indicating an essential role of increased adenosine in penile fibrosis and a novel therapeutic possibility for this serious complication. Subsequently, we identified that both mice models share a similar fibrotic gene expression profile in penile tissue (including procollagen I, TGF-β1, and plasminogen activator inhibitor-1 mRNA), suggesting that they share similar signaling pathways for progression to penile fibrosis. Thus, in an effort to decipher specific cell types and underlying mechanism responsible for adenosine-mediated penile fibrosis, we purified corpus cavernosal fibroblast cells (CCFCs), the major cell type involved in this process, from wild-type mice. Quantitative RT-PCR showed that the major receptor expressed in these cells is the adenosine receptor A2BR. Based on this fact, we further purified CCFCs from A2BR-deficient mice and demonstrated that A2BR is essential for excess adenosine-mediated penile fibrosis. Finally, we revealed that TGF-β functions downstream of the A2BR to increase CCFC collagen secretion and proliferation. Overall, our studies identify an essential role of increased adenosine in the pathogenesis of penile fibrosis via A2BR signaling and

  9. Association between Genetic Variation in the Oxytocin Receptor Gene and Emotional Withdrawal, but not between Oxytocin Pathway Genes and Diagnosis in Psychotic Disorders

    PubMed Central

    Haram, Marit; Tesli, Martin; Bettella, Francesco; Djurovic, Srdjan; Andreassen, Ole Andreas; Melle, Ingrid

    2015-01-01

    Social dysfunction is common in patients with psychotic disorders. Oxytocin is a neuropeptide with a central role in social behavior. This study aims to explore the relationship between oxytocin pathway genes and symptoms related to social dysfunction in patients with psychotic disorders. We performed association analyses between four oxytocin pathway genes (OXT, OXTR, AVP, and CD38) and four areas of social behavior-related psychopathology as measured by Positive and Negative Syndrome Scale. For this purpose, we used both a polygenic risk score (PGRS) and single OXTR candidate single nucleotide polymorphism previously reported in the literature (rs53576, rs237902, and rs2254298). A total of 734 subjects with DSM-IV psychotic spectrum disorders and 420 healthy controls were included. Oxytocin pathway PGRSs were calculated based on the independent Psychiatric Genomics Consortium study sample. There was a significant association between symptom of Emotional Withdrawal and the previously reported OXTR risk allele A in rs53576. No significant associations between oxytocin pathway gene variants and a diagnosis of psychotic disorder were found. Our findings indicate that while oxytocin pathway genes do not appear to contribute to the susceptibility to psychotic disorders, variations in the OXTR gene might play a role in the development of impaired social behavior. PMID:25667571

  10. Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells.

    PubMed

    Lu, Jing; Reese, Joshua; Zhou, Ying; Hirsch, Emmet

    2015-02-01

    Parturition is an inflammatory process mediated to a significant extent by macrophages. Progesterone (P4) maintains uterine quiescence in pregnancy, and a proposed functional withdrawal of P4 classically regulated by nuclear progesterone receptors (nPRs) leads to labor. P4 can affect the functions of macrophages despite the reported lack of expression of nPRs in these immune cells. Therefore, in this study we investigated the effects of the activation of the putative membrane-associated PR on the function of macrophages (a key cell for parturition) and discuss the implications of these findings for pregnancy and parturition. In murine macrophage cells (RAW 264.7), activation of mPRs by P4 modified to be active only extracellularly by conjugation to BSA (P4BSA, 1.0×10(-7) mol/l) caused a pro-inflammatory shift in the mRNA expression profile, with significant upregulation of the expression of cyclooxygenase 2 (COX2 (Ptgs2)), Il1B, and Tnf and downregulation of membrane progesterone receptor alpha (Paqr7) and oxytocin receptor (Oxtr). Pretreatment with PD98059, a MEK1/2 inhibitor, significantly reduced P4BSA-induced expression of mRNA of Il1B, Tnf, and Ptgs2. Inhibition of protein kinase A (PKA) by H89 blocked P4BSA-induced expression of Il1B and Tnf mRNA. P4BSA induced rapid phosphorylation of MEK1/2 and CREB (a downstream target of PKA). This phosphorylation was inhibited by pretreatment with PD98059 and H89, respectively, revealing that MEK1/2 and PKA are two of the components involved in mPR signaling. Taken together, these results indicate that changes in membrane progesterone receptor alpha expression and signaling in macrophages are associated with the inflammatory responses; and that these changes might contribute to the functional withdrawal of P4 related to labor. PMID:25472814

  11. GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of μ-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors*

    PubMed Central

    Moulédous, Lionel; Froment, Carine; Dauvillier, Stéphanie; Burlet-Schiltz, Odile; Zajac, Jean-Marie; Mollereau, Catherine

    2012-01-01

    Neuropeptide FF (NPFF) interacts with specific receptors to modulate opioid functions in the central nervous system. On dissociated neurons and neuroblastoma cells (SH-SY5Y) transfected with NPFF receptors, NPFF acts as a functional antagonist of μ-opioid (MOP) receptors by attenuating the opioid-induced inhibition of calcium conductance. In the SH-SY5Y model, MOP and NPFF2 receptors have been shown to heteromerize. To understand the molecular mechanism involved in the anti-opioid activity of NPFF, we have investigated the phosphorylation status of the MOP receptor using phospho-specific antibody and mass spectrometry. Similarly to direct opioid receptor stimulation, activation of the NPFF2 receptor by [d-Tyr-1-(NMe)Phe-3]NPFF (1DMe), an analog of NPFF, induced the phosphorylation of Ser-377 of the human MOP receptor. This heterologous phosphorylation was unaffected by inhibition of second messenger-dependent kinases and, contrarily to homologous phosphorylation, was prevented by inactivation of Gi/o proteins by pertussis toxin. Using siRNA knockdown we could demonstrate that 1DMe-induced Ser-377 cross-phosphorylation and MOP receptor loss of function were mediated by the G protein receptor kinase GRK2. In addition, mass spectrometric analysis revealed that the phosphorylation pattern of MOP receptors was qualitatively similar after treatment with the MOP agonist Tyr-d-Ala-Gly (NMe)-Phe-Gly-ol (DAMGO) or after treatment with the NPFF agonist 1DMe, but the level of multiple phosphorylation was more intense after DAMGO. Finally, NPFF2 receptor activation was sufficient to recruit β-arrestin2 to the MOP receptor but not to induce its internalization. These data show that NPFF-induced heterologous desensitization of MOP receptor signaling is mediated by GRK2 and could involve transphosphorylation within the heteromeric receptor complex. PMID:22375000

  12. GRK2 protein-mediated transphosphorylation contributes to loss of function of μ-opioid receptors induced by neuropeptide FF (NPFF2) receptors.

    PubMed

    Moulédous, Lionel; Froment, Carine; Dauvillier, Stéphanie; Burlet-Schiltz, Odile; Zajac, Jean-Marie; Mollereau, Catherine

    2012-04-13

    Neuropeptide FF (NPFF) interacts with specific receptors to modulate opioid functions in the central nervous system. On dissociated neurons and neuroblastoma cells (SH-SY5Y) transfected with NPFF receptors, NPFF acts as a functional antagonist of μ-opioid (MOP) receptors by attenuating the opioid-induced inhibition of calcium conductance. In the SH-SY5Y model, MOP and NPFF(2) receptors have been shown to heteromerize. To understand the molecular mechanism involved in the anti-opioid activity of NPFF, we have investigated the phosphorylation status of the MOP receptor using phospho-specific antibody and mass spectrometry. Similarly to direct opioid receptor stimulation, activation of the NPFF(2) receptor by [D-Tyr-1-(NMe)Phe-3]NPFF (1DMe), an analog of NPFF, induced the phosphorylation of Ser-377 of the human MOP receptor. This heterologous phosphorylation was unaffected by inhibition of second messenger-dependent kinases and, contrarily to homologous phosphorylation, was prevented by inactivation of G(i/o) proteins by pertussis toxin. Using siRNA knockdown we could demonstrate that 1DMe-induced Ser-377 cross-phosphorylation and MOP receptor loss of function were mediated by the G protein receptor kinase GRK2. In addition, mass spectrometric analysis revealed that the phosphorylation pattern of MOP receptors was qualitatively similar after treatment with the MOP agonist Tyr-D-Ala-Gly (NMe)-Phe-Gly-ol (DAMGO) or after treatment with the NPFF agonist 1DMe, but the level of multiple phosphorylation was more intense after DAMGO. Finally, NPFF(2) receptor activation was sufficient to recruit β-arrestin2 to the MOP receptor but not to induce its internalization. These data show that NPFF-induced heterologous desensitization of MOP receptor signaling is mediated by GRK2 and could involve transphosphorylation within the heteromeric receptor complex. PMID:22375000

  13. Cotranscriptional Recruitment to the mRNA Export Receptor Mex67p Contributes to Nuclear Pore Anchoring of Activated Genes▿

    PubMed Central

    Dieppois, Guennaelle; Iglesias, Nahid; Stutz, Françoise

    2006-01-01

    Transcription activation of some Saccharomyces cerevisiae genes is paralleled by their repositioning to the nuclear periphery, but the mechanism underlying gene anchoring is poorly defined. We show that the nuclear pore complex-associated Mlp1p and the shuttling mRNA export receptor Mex67p contribute to the stable association of the activated GAL10 and HSP104 genes with the nuclear periphery. However, we find no obligatory link between gene positioning and gene expression. Furthermore, gene anchoring correlates with the cotranscriptional recruitment of Mex67p to transcribing genes. Notably, the association of Mex67p with chromatin is not mediated by RNA. Interestingly, a mutant GAL2 gene lacking the coding region is still able to recruit Mex67p upon transcriptional activation and to relocate to the nuclear periphery. Together these data suggest that, at least for GAL2, nascent messenger ribonucleoprotein does not play a major role in gene anchoring and that the early recruitment of Mex67p contributes to gene repositioning by virtue of an RNA-independent process. PMID:16954382

  14. Ryanodine receptors selectively contribute to the formation of taste-evoked calcium signals in mouse taste cells

    PubMed Central

    Rebello, Michelle R.; Medler, Kathryn F.

    2010-01-01

    The peripheral taste system uses multiple signaling pathways to transduce a stimulus into an output signal that activates afferent neurons. All of these signaling pathways depend on transient increases in intracellular calcium but the current understanding of these calcium signals is not well-developed. Using molecular and physiological techniques, this study establishes that ryanodine receptors (RyRs), specifically isoform 1, are expressed in taste cells and that their physiological function differs among cell types employing different signaling pathways. RyR1 contributes to some taste-evoked signals that rely on calcium release from internal stores but can also supplement the calcium signal that is initiated by opening VGCCs. In taste cells expressing both signaling pathways, RyR1 contributes to the depolarization-induced calcium signal but not to the calcium signal that depends on calcium release from stores. These data suggest that RyR1 is an important regulator of calcium signaling and that its physiological role in taste cells is dictated by the nature of the calcium signaling mechanisms expressed. PMID:20955474

  15. Progesterone receptor isoforms PRA and PRB differentially contribute to breast cancer cell migration through interaction with focal adhesion kinase complexes

    PubMed Central

    Bellance, Catherine; Khan, Junaid A.; Meduri, Geri; Guiochon-Mantel, Anne; Lombès, Marc; Loosfelt, Hugues

    2013-01-01

    Progesterone receptor (PR) and progestins affect mammary tumorigenesis; however, the relative contributions of PR isoforms A and B (PRA and PRB, respectively) in cancer cell migration remains elusive. By using a bi-inducible MDA-MB-231 breast cancer cell line expressing PRA and/or PRB, we analyzed the effect of conditional PR isoform expression. Surprisingly, unliganded PRB but not PRA strongly enhanced cell migration as compared with PR(–) cells. 17,21-Dimethyl-19-norpregna-4,9-dien-3,20-dione (R5020) progestin limited this effect and was counteracted by the antagonist 11β-(4-dimethyl­amino)­phenyl-17β-hydroxy-17-(1-propynyl)­estra-4,9-dien-3-one (RU486). Of importance, PRA coexpression potentiated PRB-mediated migration, whereas PRA alone was ineffective. PR isoforms differentially regulated expressions of major players of cell migration, such as urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor type 1, uPA receptor (uPAR), and β1-integrin, which affect focal adhesion kinase (FAK) signaling. Moreover, unliganded PRB but not PRA enhanced FAK Tyr397 phosphorylation and colocalized with activated FAK in cell protrusions. Because PRB, as well as PRA, coimmunoprecipitated with FAK, both isoforms can interact with FAK complexes, depending on their respective nucleocytoplasmic trafficking. In addition, FAK degradation was coupled to R5020-dependent turnovers of PRA and PRB. Such an effect of PRB/PRA expression on FAK signaling might thus affect adhesion/motility, underscoring the implication of PR isoforms in breast cancer invasiveness and metastatic evolution with underlying therapeutic outcomes. PMID:23485561

  16. Recognition and Activation Domains Contribute to Allele-Specific Responses of an Arabidopsis NLR Receptor to an Oomycete Effector Protein

    PubMed Central

    Steinbrenner, Adam D.; Goritschnig, Sandra; Staskawicz, Brian J.

    2015-01-01

    In plants, specific recognition of pathogen effector proteins by nucleotide-binding leucine-rich repeat (NLR) receptors leads to activation of immune responses. RPP1, an NLR from Arabidopsis thaliana, recognizes the effector ATR1, from the oomycete pathogen Hyaloperonospora arabidopsidis, by direct association via C-terminal leucine-rich repeats (LRRs). Two RPP1 alleles, RPP1-NdA and RPP1-WsB, have narrow and broad recognition spectra, respectively, with RPP1-NdA recognizing a subset of the ATR1 variants recognized by RPP1-WsB. In this work, we further characterized direct effector recognition through random mutagenesis of an unrecognized ATR1 allele, ATR1-Cala2, screening for gain-of-recognition phenotypes in a tobacco hypersensitive response assay. We identified ATR1 mutants that a) confirm surface-exposed residues contribute to recognition by RPP1, and b) are recognized by and activate the narrow-spectrum allele RPP1-NdA, but not RPP1-WsB, in co-immunoprecipitation and bacterial growth inhibition assays. Thus, RPP1 alleles have distinct recognition specificities, rather than simply different sensitivity to activation. Using chimeric RPP1 constructs, we showed that RPP1-NdA LRRs were sufficient for allele-specific recognition (association with ATR1), but insufficient for receptor activation in the form of HR. Additional inclusion of the RPP1-NdA ARC2 subdomain, from the central NB-ARC domain, was required for a full range of activation specificity. Thus, cooperation between recognition and activation domains seems to be essential for NLR function. PMID:25671309

  17. Differential Contributions of Dopaminergic D1-like and D2-like Receptors to Cognitive Function in Rhesus Monkeys

    PubMed Central

    Von Huben, Stefani N.; Davis, Sophia A.; Lay, Christopher C.; Katner, Simon N.; Crean, Rebecca D.

    2007-01-01

    Rationale Dopaminergic neurotransmission is critically involved in many aspects of complex behavior and cognition beyond reward/reinforcement and motor function. Mental and behavioral disorders associated with major disruptions of dopamine neurotransmission, including schizophrenia, Attention Deficit/Hyperactivity Disorder, Parkinson’s Disease, Huntington’s Disease and substance abuse, produce constellations of neuropsychological deficits in learning, memory and attention in addition to other defining symptoms. Objective To delineate the role dopaminergic D1-like and D2-like receptor subtypes play in complex brain functions. Methods Monkeys (N=6) were trained on cognitive tests adapted from a human neuropsychological assessment battery (CANTAB; CAmbridge Neuropsychological Test Automated Battery). The battery included tests of spatial working memory (self-ordered spatial search task, SOSS), visuo-spatial associative memory and learning (visuo-spatial paired associates learning task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function (bimanual motor skill task, BMS; rotating turntable task, RTT) were also included. Effects of the dopamine D2-like antagonist raclopride (10-56 μg/kg, i.m.) and the D1-like antagonist SCH23390 (SCH; 3.2-56 μg/kg, i.m.) on cognitive performance were then determined. Results Deficits on PR, RTT and BMS performance were observed after both raclopride and SCH23390. Spatial working memory accuracy was reduced to a greater extent by raclopride than by SCH which was unexpected, given prior reports on the involvement of D1 signaling for spatial working memory in monkeys. Deficits were observed on vsPAL performance after raclopride, but not after SCH23390. Conclusions The intriguing results suggest a greater contribution of D2-like over D1-like receptors to both spatial working memory and object-location associative memory. PMID:16538469

  18. The contributions of muscarinic receptors and changes in plasma aldosterone levels to the anti-hypertensive effect of Tulbaghia violacea

    PubMed Central

    2013-01-01

    Background Tulbaghia violacea Harv. (Alliaceae) is used to treat various ailments, including hypertension (HTN) in South Africa. This study aims to evaluate the contributions of muscarinic receptors and changes in plasma aldosterone levels to its anti-hypertensive effect. Methods In the acute experiments, methanol leaf extracts (MLE) of T. violacea (30–120 mg/kg), muscarine (0.16 -10 μg/kg), and atropine (0.02 - 20.48 mg/kg), and/or the vehicle (dimethylsulfoxide (DMSO) and normal saline (NS)) were respectively and randomly administered intravenously in a group of spontaneously hypertensive (SHR) weighing 300 to 350 g and aged less than 5 months. Subsequently, T. violacea (60 mg/kg) or muscarine (2.5 μg/kg) was infused into eight SHRs, 20 min after atropine (5.12 mg/kg) pre-treatment. In the chronic (21 days) experiments, the SHRs were randomly divided into three groups, and given the vehicle (0.2 ml/day of DMSO and NS), T. violacea (60 mg/kg/day) and captopril (10 mg/kg/day) respectively into the peritoneum, to investigate their effects on blood pressure (BP), heart rate (HR), and plasma aldosterone levels. Systolic BP and HR were measured using tail-cuff plethysmography during the intervention. BP and HR were measured via a pressure transducer connecting the femoral artery and the Powerlab at the end of each intervention in the acute experiment; and on day 22 in the chronic experiment. Results In the acute experiments, T. violacea, muscarine, and atropine significantly (p < 0.05) reduced BP dose-dependently. T. violacea and muscarine produced dose-dependent decreases in HR, while the effect of atropine on HR varied. After atropine pre-treatment, dose-dependent increases in BP and HR were observed with T. violacea; while the BP and HR effects of muscarine were nullified. In the chronic experiments, the T. violacea-treated and captropril-treated groups had signicantly lower levels of aldosterone in plasma when compared to vehicle

  19. Immobilization with Atrophy Induces Increased Expression of Neuronal Nicotinic α7 Acetylcholine Receptors in Muscle Contributing to Neurotransmission

    PubMed Central

    Lee, Sangseok; Yang, Hong-seuk; Sasakawa, Tomoki; Khan, Mohammed A. S.; Khatri, Ashok; Kaneki, Masao; Jeevendra Martyn, J. A.

    2014-01-01

    Background Mature acetylcholine receptor (AChR) isoform normally mediates muscle contraction. The hypothesis that α7AChRs upregulate during immobilization and contribute to neurotransmission was tested pharmacologically using specific blockers to mature (waglerin-1), immature (αA-OIVA), and α7AChRs methyllycaconitine, and non-specific muscle AChR antagonist, α-bungarotoxin. Methods Mice were immobilized; contralateral limb was control. Fourteen days later, anesthetized mice were mechanically ventilated. Nerve-stimulated tibialis muscle contractions on both sides were recorded, and blockers enumerated above sequentially administered via jugular vein. Data are mean ± S.E. Results Immobilization (N=7) induced tibialis muscle atrophy (40.6 ± 2.8 vs 52.1 ± 2.0 mg, p<0.01) and decrease of twitch tension (34.8 ± 1.1 vs. 42.9 ± 1.5 g, p< 0.01). Waglerin-1 (0.3 ± 0.05 μg/g) significantly (p=0.001, N=9) depressed twitch tension on contralateral (≥ 97%) versus immobilized side (~45%). Additional waglerin-1 (total dose 1.06 ± 0.12 μg/g or ~15.0 X ED50 in normals) could not depress twitch ≥ 80% on immobilized side. Immature AChR blocker, αA-OIVA (17.0 ± 0.25 μg/g) did not change tension bilaterally. Administration of α-bungarotoxin (N=4) or methyllycaconitine (N=3) caused ≥ 96% suppression of the remaining twitch tension on immobilized side. Methyllycaconitine, administered first (N=3), caused equipotent inhibition by waglerin-1 on both sides. Protein expression of α7AChRs was significantly (N=3, p<0.01) increased on the immobilized side. Conclusions Ineffectiveness of waglerin-1 suggests the twitch tension during immobilization is maintained by receptors other than mature AChRs. Since αA-OIVA caused no changes, immature AChRs contribute minimally to neurotransmission. During immobilization ~20% of twitch tension is maintained by upregulation of α-bungarotoxin- and methyllycaconitine-sensitive α7AChRs. PMID:24126263

  20. Differential Methylation of the Oxytocin Receptor Gene in Patients with Anorexia Nervosa: A Pilot Study

    PubMed Central

    Kim, Mi Jeong; Treasure, Janet

    2014-01-01

    Background and Aim Recent studies in patients with anorexia nervosa suggest that oxytocin may be involved in the pathophysiology of anorexia nervosa. We examined whether there was evidence of variation in methylation status of the oxytocin receptor (OXTR) gene in patients with anorexia nervosa that might account for these findings. Methods We analyzed the methylation status of the CpG sites in a region from the exon 1 to the MT2 regions of the OXTR gene in buccal cells from 15 patients and 36 healthy women using bisulfite sequencing. We further examined whether methylation status was associated with markers of illness severity or form. Results We identified six CpG sites with significant differences in average methylation levels between the patient and control groups. Among the six differentially methylated CpG sites, five showed higher than average methylation levels in patients than those in the control group (64.9–88.8% vs. 6.6–45.0%). The methylation levels of these five CpG sites were negatively associated with body mass index (BMI). BMI, eating disorders psychopathology, and anxiety were identified in a regression analysis as factors affecting the methylation levels of these CpG sites with more variation accounted for by BMI. Conclusions Epigenetic misregulation of the OXTR gene may be implicated in anorexia nervosa, which may either be a mechanism linking environmental adversity to risk or may be a secondary consequence of the illness. PMID:24523928

  1. Polymorphism of the Oxytocin Receptor Gene Modulates Behavioral and Attitudinal Trust among Men but Not Women

    PubMed Central

    Nishina, Kuniyuki; Takagishi, Haruto; Inoue-Murayama, Miho; Takahashi, Hidehiko; Yamagishi, Toshio

    2015-01-01

    A relationship between the oxytocin receptor gene (OXTR) and behavioral and attitudinal trust has been suggested, but the nature of this relationship has not yet been established. We obtained behavioral trust data from 470 Japanese participants (242 women) aged 20–59 years, together with their levels of general trust and personality traits (NEO-FFI). Saliva buccal swabs were collected from 411 of these 470 participants and used for genotyping of OXTR rs53576. Our participants were found to have more AA alleles (40%) than GG alleles (12%). The GG men were more trusting and also rated higher on attitudinal trust than AA men, and this difference did not diminish when personality traits were controlled for. However, this pattern was not observed among women. In addition, controlling for attitudinal trust reduced the difference in behavioral trust among men to a non-significant level, but the difference in attitudinal trust remained significant when behavioral trust was controlled. These results indicate that the OXTR genotype affects attitudinal trust as part of an individual’s relatively stable disposition, and further affects behavioral trust through changes in attitudinal trust. PMID:26444016

  2. Amygdala responses to salient social cues vary with oxytocin receptor genotype in youth.

    PubMed

    Marusak, Hilary A; Furman, Daniella J; Kuruvadi, Nisha; Shattuck, David W; Joshi, Shantanu H; Joshi, Anand A; Etkin, Amit; Thomason, Moriah E

    2015-12-01

    Depression, anxiety, and posttraumatic stress disorder are linked to altered limbic morphology, dysregulated neuroendocrine function, and heightened amygdala responses to salient social cues. Oxytocin appears to be a potent modulator of amygdala reactivity and neuroendocrine responses to psychosocial stress. Given these stress regulatory effects, there is increasing interest in understanding the role of oxytocin in vulnerability to stress-related clinical disorders. The present study examines the impact of a common functional variant within the oxytocin receptor (OXTR) gene (rs2254298) on structure and function of the amygdala in a high-risk sample of urban, low-income, minority youth with a high incidence of early life stress (ELS). Compared to G/G homozygotes, youth carrying the OXTR A-allele showed increased amygdala volume, reduced behavioral performance, and heightened amygdala response during two functional magnetic resonance imaging (fMRI) tasks that involved viewing socially-relevant face stimuli. Higher amygdala response was related to ELS in A-allele carriers but not G/G homozygotes. These findings underscore a series of relations among a common oxytocin system gene variant, ELS exposure, and structure and function of the amygdala in early life. Heightened amygdala response to salient social cues in OXTR A-allele carriers may elevate risk for emotional psychopathology by increasing amygdala involvement in disambiguating environmental cues, particularly for individuals with ELS. PMID:26477647

  3. Neural correlate of autistic-like traits and a common allele in the oxytocin receptor gene.

    PubMed

    Saito, Yuki; Suga, Motomu; Tochigi, Mamoru; Abe, Osamu; Yahata, Noriaki; Kawakubo, Yuki; Liu, Xiaoxi; Kawamura, Yoshiya; Sasaki, Tsukasa; Kasai, Kiyoto; Yamasue, Hidenori

    2014-10-01

    Sub-clinical autistic-like traits (ALTs) are continuously distributed in the general population and genetically linked to autism. Although identifying the neurogenetic backgrounds of ALTs might enhance our ability to identify those of autism, they are largely unstudied. Here, we have examined the neuroanatomical basis of ALTs and their association with the oxytocin receptor gene (OXTR) rs2254298A, a known risk allele for autism in Asian populations which has also been implicated in limbic-paralimbic brain structures. First, we extracted a four-factor structure of ALTs, as measured using the Autism-Spectrum Quotient, including 'prosociality', 'communication', 'details/patterns' and 'imagination' in 135 neurotypical adults (79 men, 56 women) to reduce the genetic heterogeneity of ALTs. Then, in the same population, voxel-based morphometry revealed that lower 'prosociality', which indicates strong ALTs, was significantly correlated to smaller regional grey matter volume in the right insula in males. Males with lower 'prosociality' also had less interregional structural coupling between the right insula and the ventral anterior cingulate cortex. Furthermore, males with OXTR rs2254298A had significantly smaller grey matter volume in the right insula. These results show that decreased volume of the insula is a neuroanatomical correlate of ALTs and a potential intermediate phenotype linking ALTs with OXTR in male subjects. PMID:23946005

  4. An oxytocin receptor polymorphism predicts amygdala reactivity and antisocial behavior in men.

    PubMed

    Waller, Rebecca; Corral-Frías, Nadia S; Vannucci, Bianca; Bogdan, Ryan; Knodt, Annchen R; Hariri, Ahmad R; Hyde, Luke W

    2016-08-01

    Variability in oxytocin (OXT) signaling is associated with individual differences in sex-specific social behavior across species. The effects of OXT signaling on social behavior are, in part, mediated through its modulation of amygdala function. Here, we use imaging genetics to examine sex-specific effects of three single-nucleotide polymorphisms in the human oxytocin receptor gene (OXTR; rs1042778, rs53576 and rs2254298) on threat-related amygdala reactivity and social behavior in 406 Caucasians. Analyses revealed that among men but not women, OXTR rs1042778 TT genotype was associated with increased right amygdala reactivity to angry facial expressions, which was uniquely related to higher levels of antisocial behavior among men. Moderated meditation analysis suggested a trending indirect effect of OXTR rs1042778 TT genotype on higher antisocial behavior via increased right amygdala reactivity to angry facial expressions in men. Our results provide evidence linking genetic variation in OXT signaling to individual differences in amygdala function. The results further suggest that these pathways may be uniquely important in shaping antisocial behavior in men. PMID:27036876

  5. Neural correlate of autistic-like traits and a common allele in the oxytocin receptor gene

    PubMed Central

    Saito, Yuki; Suga, Motomu; Tochigi, Mamoru; Abe, Osamu; Yahata, Noriaki; Kawakubo, Yuki; Liu, Xiaoxi; Kawamura, Yoshiya; Sasaki, Tsukasa; Kasai, Kiyoto

    2014-01-01

    Sub-clinical autistic-like traits (ALTs) are continuously distributed in the general population and genetically linked to autism. Although identifying the neurogenetic backgrounds of ALTs might enhance our ability to identify those of autism, they are largely unstudied. Here, we have examined the neuroanatomical basis of ALTs and their association with the oxytocin receptor gene (OXTR) rs2254298A, a known risk allele for autism in Asian populations which has also been implicated in limbic–paralimbic brain structures. First, we extracted a four-factor structure of ALTs, as measured using the Autism-Spectrum Quotient, including ‘prosociality’, ‘communication’, ‘details/patterns’ and ‘imagination’ in 135 neurotypical adults (79 men, 56 women) to reduce the genetic heterogeneity of ALTs. Then, in the same population, voxel-based morphometry revealed that lower ‘prosociality’, which indicates strong ALTs, was significantly correlated to smaller regional grey matter volume in the right insula in males. Males with lower ‘prosociality’ also had less interregional structural coupling between the right insula and the ventral anterior cingulate cortex. Furthermore, males with OXTR rs2254298A had significantly smaller grey matter volume in the right insula. These results show that decreased volume of the insula is a neuroanatomical correlate of ALTs and a potential intermediate phenotype linking ALTs with OXTR in male subjects. PMID:23946005

  6. Inter-residue coupling contributes to high-affinity subtype-selective binding of α-bungarotoxin to nicotinic receptors

    PubMed Central

    Sine, Steven M.; Huang, Sun; Li, Shu-Xing; daCOSTA, Corrie J. B.; Chen, Lin

    2014-01-01

    The crystal structure of a pentameric α7 ligand-binding domain chimaera with bound α-btx (α-bungarotoxin) showed that of the five conserved aromatic residues in α7, only Tyr184 in loop C of the ligand-binding site was required for high-affinity binding. To determine whether the contribution of Tyr184 depends on local residues, we generated mutations in an α7/5HT3A (5-hydroxytryptamine type 3A) receptor chimaera, individually and in pairs, and measured 125I-labelled α-btx binding. The results show that mutations of individual residues near Tyr184 do not affect α-btx affinity, but pairwise mutations decrease affinity in an energetically coupled manner. Kinetic measurements show that the affinity decreases arise through increases in the α-btx dissociation rate with little change in the association rate. Replacing loop C in α7 with loop C from the α-btx-insensitive α2 or α3 subunits abolishes high-affinity α-btx binding, but preserves acetylcholine-elicited single channel currents. However, in both the α2 and α3 construct, mutating either residue that flanks Tyr184 to its α7 counterpart restores high-affinity α-btx binding. Analogously, in α7, mutating both residues that flank Tyr184 to the α2 or α3 counterparts abolishes high-affinity α-btx binding. Thus interaction between Tyr184 and local residues contributes to high-affinity subtype-selective α-btx binding. PMID:23802200

  7. Plasticity in the contribution of T cell receptor variable region residues to binding of peptide-HLA-A2 complexes

    PubMed Central

    Smith, Sheena N.; Sommermeyer, Daniel; Piepenbrink, Kurt H.; Blevins, Sydney J.; Bernhard, Helga; Uckert, Wolfgang; Baker, Brian M.; Kranz, David M.

    2013-01-01

    One hypothesis to account for MHC-restriction by T cell receptors (TCRs) holds that there are several evolutionary-conserved residues in TCR variable regions that contact MHC. While this ‘germline-codon’ hypothesis is supported by various lines of evidence, it has been difficult to test. The difficulty stems in part from the fact that TCRs exhibit low affinities for pep/MHC, thus limiting the range of binding energies that can be assigned to these key interactions using mutational analyses. To measure the magnitude of binding energies involved, here we used high-affinity TCRs engineered by mutagenesis of CDR3. The TCRs included a high-affinity, MART-1/HLA-A2-specific single-chain TCR and two other high-affinity TCRs that all contain the same Vα (HLA-A2), with different peptides and Vβ regions. Mutational analysis of residues in CDR1 and CDR2 of the three Vα2 regions showed the importance of the key ‘germline codon” residue Y51. However, two other proposed key residues showed significant differences among the TCRs in their relative contributions to binding. Using single-position, yeast-display libraries in two of the key residues, MART-1/HLA-A2 selections also revealed strong preferences for wild-type ‘germline codon’ residues, but several alternative residues could also accommodate binding and hence, MHC-restriction. Thus, although a single residue (Y51) could account for a proportion of the energy associated with positive selection (i.e. MHC-restriction), there is significant plasticity in requirements for particular side-chains in CDR1 and CDR2 and in their relative binding contributions among different TCRs. PMID:23954306

  8. Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma

    PubMed Central

    Takino, Jun-ichi; Nagamine, Kentaro; Hori, Takamitsu; Sakasai-Sakai, Akiko; Takeuchi, Masayoshi

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC. PMID:26483867

  9. The contribution of nasal receptors to the cardiac response to diving in restrained and unrestrained redhead ducks (Aythya americana).

    PubMed

    Furilla, R A; Jones, D R

    1986-03-01

    In restrained redhead ducks, forced submergence caused heart rate to fall from 100 +/- 3 beats min-1 (mean +/- S.E.M., N = 12) to a stable underwater rate of 35 +/- 4 beats min-1 (N = 12) within 5 s after submergence. Bradycardia was unaffected by breathing oxygen before a dive, but was virtually eliminated by local anaesthesia of the narial region. In contrast, in a dabbling duck (Anas platyrhynchos) bradycardia in short dives was eliminated by breathing oxygen before a dive. In unrestrained diving, on a man-made pond, heart rate in redheads diving voluntarily (y) was related to pre-dive heart rate (x) by the equation y = 76 + 0.29 +/- 0.05x +/- 17 (r2 = 0.71). Chasing, to induce submergence, had variable effects on this relationship. Local anaesthesia of the narial region inhibited voluntary diving but heart rates in chase-induced dives after nasal blockade were significantly higher, by 10-30%, than those obtained from untreated ducks in chase-induced dives. Breathing oxygen before voluntary dives had no apparent effect on heart rate after 2-5 s submergence. Voluntary head submersion by dabbling ducks caused no change in heart rate. We conclude that nasal receptors make only a minor contribution to cardiac responses in unrestrained dives, compared with forced dives, in diving ducks. Furthermore, these results show that little can be learned about cardiac responses in free diving ducks from studies of forced dives in dabblers or divers. PMID:3958677

  10. Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy.

    PubMed

    Hu, Qidi; Ren, Xiangpeng; Liu, Ya; Li, Zhihui; Zhang, Liping; Chen, Xingjun; He, Chaoxiang; Chen, Jiang-Fan

    2016-09-01

    Synucleinopathy is characterized by abnormal accumulation of misfolded α-synuclein (α-Syn)-positive cytoplasmic inclusions and by neurodegeneration and cognitive impairments, but the pathogenesis mechanism of synucleinopathy remains to be defined. Using a transmission model of synucleinopathy by intracerebral injection of preformed A53T α-Syn fibrils, we investigated whether aberrant adenosine A2A receptor (A2AR) signaling contributed to pathogenesis of synucleinopathy. We demonstrated that intra-hippocampal injection of preformed mutant α-Syn fibrils triggered a striking and selective induction of A2AR expression which was closely co-localized with pSer129 α-Syn-rich inclusions in neurons and glial cells of hippocampus. Importantly, by abolishing aberrant A2AR signaling triggered by mutant α-Syn, genetic deletion of A2ARs blunted a cascade of pathological events leading to synucleinopathy, including pSer129 α-Syn-rich and p62-positive aggregates, NF-κB activation and astrogliosis, apoptotic neuronal cell death and working memory deficits without affecting motor activity. These findings define α-Syn-triggered aberrant A2AR signaling as a critical pathogenesis mechanism of synucleinopathy with dual controls of cognition and neurodegeneration by modulating α-Syn aggregates. Thus, aberrant A2AR signaling represents a useful biomarker as well as a therapeutic target of synucleinopathy. PMID:27342081