Corticotropin-releasing Hormone Receptor Gene Research Articles

Novel corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) linkage to and association with polycystic ovary syndrome

BackgroundWomen with polycystic ovarian syndrome (PCOS) have increased hypothalamic–pituitary–adrenal (HPA) axis activation, pro-inflammatory mediators, and psychological distress in response to stressors. In women with PCOS, the corticotropin-releasing hormone (CRH) induces an exaggerated HPA response, possibly mediated by one of the CRH receptors (CRHR1 or CRHR2). Both CRHR1 and CRHR2 are implicated in insulin secretion, and variants in CRHR1 and CRHR2 genes may predispose to the mental-metabolic risk for PCOS.MethodsWe phenotyped 212 Italian families with type 2 diabetes (T2D) for PCOS following the Rotterdam diagnostic criteria. We analyzed within CRHR1 and CRHR2 genes, respectively, 36 and 18 microarray-variants for parametric linkage to and/or linkage disequilibrium (LD) with PCOS under the recessive with complete penetrance (R1) and dominant with complete penetrance (D1) models. Subsequentially, we ran a secondary analysis under the models dominant with incomplete penetrance (D2) and recessive with incomplete penetrance (R2).ResultsWe detected 22 variants in CRHR1 and 1 variant in CRHR2 significantly (p < 0.05) linked to or in LD with PCOS across different inheritance models.ConclusionsThis is the first study to report CRHR1 and CRHR2 as novel risk genes in PCOS. In silico analysis predicted that the detected CRHR1 and CRHR2 risk variants promote negative chromatin activation of their related genes in the ovaries, potentially affecting the female cycle and ovulation. However, CRHR1- and CRHR2-risk variants might also lead to hypercortisolism and confer mental-metabolic pleiotropic effects. Functional studies are needed to confirm the pathogenicity of genes and related variants.

Effects of prebiotics on intestinal physiology, neuropsychological function, and exercise capacity of mice with sleep deprivation

People suffered from insufficient or disrupted sleep due to night shifts, work pressure, and irregular lifestyles. Sleep deprivation caused by inadequate quantity or quality of sleep has been associated with not only increased risk of metabolic diseases, gut dysbiosis, and emotional disorders but also decreased work and exercise performance. In this study, we used the modified multiple platform method (MMPM) to induce pathological and psychological characteristics of sleep deprivation with C57BL/6J male mice, and investigated whether supplementing a prebiotics mixture of short-chain galactooligosaccharides (scGOS) and long-chain fructooligosaccharides (lcFOS) (9:1 ratio) could improve the impacts of sleep deprivation on intestinal physiology, neuropsychological function, inflammation, circadian rhythm, and exercise capacity. Results showed that sleep deprivation caused intestinal inflammation (increased TNFA and IL1B) and decreased intestinal permeability with a significant decrease in the tight junction genes (OCLN, CLDN1, TJP1, and TJP2) of intestine and brain. The prebiotics significantly increased the content of metabolite short-chain fatty acids (acetate and butyrate) while recovering the expression of indicated tight junction genes. In hypothalamus and hippocampus, clock (BMAL1 and CLOCK) and tight junction (OCLN and TJP2) genes were improved by prebiotics, and corticotropin-releasing hormone receptor genes, CRF1 and CRF2, were also significantly regulated for mitigation of depression and anxiety caused by sleep deprivation. Also, prebiotics brought significant benefits on blood sugar homeostasis and improvement of exercise performance. Functional prebiotics could improve physiological modulation, neuropsychological behaviors, and exercise performance caused by sleep deprivation, possibly through regulation of inflammation and circadian rhythm for health maintenance. However, the microbiota affected by prebiotics and sleep deprivation should warrant further investigation.

The interaction of corticotropin-releasing hormone receptor gene and early life stress on emotional empathy

Early life stress (ELS) is associated with increased vulnerability for depression, changes to the corticotropin-releasing hormone (CRH) system and structural and functional changes in hippocampus. Single nucleotide polymorphisms in the CRH receptor 1 (CRHR1) gene interact with ELS to predict depression, cognitive functions and hippocampal activity. Social cognition has been related to hippocampal function and might be crucial for maintaining mental health. However, the interaction of CRHR1 gene variation and ELS on social cognition has not been investigated yet. We assessed social cognition in 502 healthy subjects to test effects of ELS and the CRHR1 gene. Participants were genotyped for rs110402 and rs242924. ELS was assessed by Childhood Trauma Questionnaire, social cognition was measured via Multifaceted Empathy Test and Empathy Quotient. Severity of ELS was associated with decreased emotional, but not cognitive empathy. Subjects with the common homozygous GG GG genotype showed decreased implicit emotional empathy after ELS exposure regardless of its severity. The results reveal that specific CRHR1 polymorphisms moderate the effect of ELS on emotional empathy. Exposure to ELS in combination with a vulnerable genotype results in impaired emotional empathy in adulthood, which might represent an early marker of increased vulnerability after ELS.

Sensitizing effect of early adversity on depressive reactions to later proximal stress: Moderation by polymorphisms in serotonin transporter and corticotropin releasing hormone receptor genes in a 20-year longitudinal study.

Previous research supports gene-environment interactions for polymorphisms in the corticotropin hormone receptor 1 gene (CRHR1) and the serotonin transporter gene linked polymorphic region (5-HTTLPR) in predicting depression, but it has rarely considered genetic influences on stress sensitization processes, whereby early adversities (EA) increase depressive reactivity to proximal stressors later in life. The current study tested a gene-environment-environment interaction (G × E × E; specifically, gene-EA-proximal stress interaction) model of depression in a 20-year longitudinal study. Participants were assessed prospectively for EA up to age 5 and recent chronic stress and depressive symptoms at age 20 and genotyped for CRHR1 single nucleotide polymorphism rs110402 and 5-HTTLPR. EA predicted stronger associations between recent chronic stress and depression, and the effect was moderated by genes. CRHR1 A alleles and 5-HTTLPR short alleles were associated with greater stress sensitization (i.e., greater depressive reactivity to chronic stress for those also exposed to high levels of EA). The results are consistent with the notion that EA exposure results in neurobiological and cognitive-emotional consequences (e.g., altered hypothalamic-pituitary-adrenal axis functioning), leading to emotional distress in the face of recent stressors among those with certain genetic characteristics, although further research is needed to explore explanatory mechanisms.

Interaction of Early Life Stress and Corticotropin-Releasing Hormone Receptor Gene: Effects on Working Memory

Early life stress (ELS) experience is associated with persisting working memory (WM) deficits; changes to the corticotropin-releasing hormone (CRH) system; and structural, functional, and epigenetic changes in the hippocampus. Single nucleotide polymorphisms in the CRH receptor 1 (CRHR1) gene interact with ELS experience to predict depression as well as neuroendocrine and neuronal reactivity. Although these findings indicate that vulnerable genotypes might also show impaired WM performance after ELS experience, no previous study investigated whether there is an interaction effect of CRHR1 polymorphisms and ELS experience on WM performance. Subjects (N = 451) were genotyped for rs110402 and rs242924 within the CRHR1 gene. We used an n-back task to investigate the hypothesis that WM performance in healthy subjects may be subtly influenced by functional differences in CRHR1 and represents an early marker of increased vulnerability after exposure to ELS. Exposure to ELS had a particularly strong impact on WM performance in subjects with the common homozygous GG GG genotype, whereas only severe exposure to ELS interfered with WM accuracy in AT carriers. Our data indicate that specific CRHR1 polymorphisms moderate the effect of ELS experience on WM performance. Exposure to ELS in combination with a vulnerable genotype results in subtle memory deficits in adulthood, which might develop before psychopathological symptoms.

Abused Children May Develop Subtle Physiological Changes

Abused Children May Develop Subtle Physiological Changes

Interaction of Childhood Maltreatment with the Corticotropin-Releasing Hormone Receptor Gene: Effects on Hypothalamic-Pituitary-Adrenal Axis Reactivity

Variation in the corticotropin-releasing hormone receptor (CRHR1) gene has been shown to interact with early life stress to predict adult depression. This study was conducted to determine whether CRHR1 polymorphisms interact with childhood maltreatment to predict hypothalamic-pituitary-adrenal (HPA) axis reactivity, which has been linked to both depression and early life stress. One hundred twenty-nine White, non-Hispanic adults completed the Childhood Trauma Questionnaire and the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test, and provided blood samples for genotyping of two CRHR1 polymorphisms. Both rs110402 and rs242924 (which were in tight linkage disequilibrium, D' = .98) showed a significant interaction with maltreatment in the prediction of cortisol response to the DEX/CRH test (p < .05). For subjects with maltreatment, the GG genotype of each single nucleotide polymorphism was associated with elevated cortisol responses to the test. Variation in the CRHR1 moderates the effect of childhood maltreatment on cortisol responses to the DEX/CRH test. Excessive HPA axis activation could represent a mechanism of interactions of risk genes with stress in the development of mood and anxiety disorders.

Overexpression of vasopressin (V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours.

The molecular mechanisms underlying ACTH-secreting tumour formation remain unknown. Transmembrane signalling pathways play an important role in several endocrine disorders including pituitary tumours. To investigate the role of the pituitary vasopressin (V3) receptor (R) in ACTH-secreting tumours we have qualitatively and quantitatively analysed its mRNA. RT-PCR, denaturing gradient gel electrophoresis and S1 nuclease protection experiments were used to analyse V3 mRNA structure in ACTH-secreting tumours. We also developed a competitive RT-PCR system to compare the levels of expression of POMC, V3 and CRH-R genes. This system used as competitor a single mutant template (termed multi-mutant) containing primers for the three genes flanking an unrelated core sequence allowing multiple quantifications from the same cDNA preparations. We analysed 12 normal pituitaries, 15 corticotroph pituitary adenomas and 6 ACTH-secreting bronchial carcinoids. The V3 mRNA structure and sequence were found to be identical in normal and tumoural pituitary indicating that the tumoural Vs mRNA codes for a normal receptor. POMC RT-PCR signals in the pituitary tumour group were approximately 7-fold higher than in the normal pituitary group. Similarly, V3 and CRH-R signal were increased in pituitary tumors (mean +/- SEM: 5.87 x 10(-6) +/- 1.73 x 10(-6), and 2.33 x 10(-4) +/- 1.4 x 10(-4), respectively), when compared to normal pituitaries (1.19 x 10(-7) +/- 2.39 x 10(-8), and 1.7 x 10(-6) +/- 4.65 x 10(-7), respectively) suggesting that these two genes are expressed at very high levels in corticotroph tumours. When expressed relative to the corresponding POMC signals, increases in V3 and CRH-R signals reached 49-fold and 137-fold, respectively, in pituitary tumours. In ACTH-secreting bronchial carcinoids V3 gene expression level was also higher than in normal pituitary, whereas CRH-R signals were detected in only 4 of the 6 tumours with wide variations. Our results show that both vasopressin and CRH receptor genes are overexpressed in ACTH-secreting pituitary tumours. They suggest that overexpression of G protein-coupled receptors may be an additional mechanism through which membrane receptors may play a role in human tumours.

Expression of proopiomelanocortin, corticotropin releasing hormone, and corticotropin releasing hormone receptor genes in human melanocytes, nevus cells, and melanoma cells

Expression of proopiomelanocortin, corticotropin releasing hormone, and corticotropin releasing hormone receptor genes in human melanocytes, nevus cells, and melanoma cells

Developmental profile of messenger RNA for the corticotropin-releasing hormone receptor in the rat limbic system

The ontogeny of corticotropin-releasing hormone (CRH) receptor messenger ribonucleic acid (mRNA) in rat brain, using in situ hybridization, is the focus of this study. The developmental profile of CRH receptor using binding assays and receptor autoradiography has been reported, but may be confounded by the presence of a binding protein. The recent cloning of the rat CRH receptor gene has permitted the use of in situ hybridization histochemistry to map the distribution of cells expressing CRH receptor mRNA in the developing brain. We used antisense 35S-labeled oligodeoxynucleotide probes for the two reported splice-variants of the CRH receptor mRNA, which yielded essentially identical localization patterns. CRH receptor mRNA was clearly detectable in infant brain starting on the second postnatal day. Signal in hippocampal CA1, CA2 and CA3a increased to 300–600% of adult levels by postnatal day 6 with a subsequent gradual decline. In the amygdala, in contrast, CRH receptor mRNA abundance increased steadily between the second and the ninth postnatal days, to levels twice higher than those in the adult. In the cortex, CRH receptor mRNA levels were high on postnatal day 2 and decreased to adult levels by day 12. Transient signal over the hypothalamic paraventricular nucleus, observed on the second postnatal day, was not evident at older ages. These results demonstrate robust synthesis of CRH receptor as early as on the second postnatal day and unique region-specific developmental profiles for CRH receptor gene expression.

Proopiomelanocortin, corticotropin releasing hormone and corticotropin releasing hormone receptor genes are expressed in human skin

Evidence is provided that human skin, the largest body organ exposed to multiple stressors, expresses proopiomelanocortin (POMC), corticotropin releasing hormone (CRH) and CRH-receptor (CRHR) genes in vivo. In vitro studies show that POMC and CRHR mRNAs are transcribed in melanocytes, cells derived from the neural crest, and in keratinocytes, cells derived from the ectoderm. CRH mRNA is transcribed in cultured melanocytes but not in keratinocytes. It is proposed that an equivalent of the ‘hypothalamus-pituitary axis’ composed of the CRH-CRHR-POMC loop is conserved in mammalian skin.

Corticotropin-releasing hormone and its receptor distribution in fetal membranes and placenta of the rhesus monkey in late gestation and labor

Maternal plasma corticotropin-Releasing Hormone (CRH) rises from midgestation to term and increases further during labor in pregnant women. The primate placenta contains both the CRH peptide and its gene and is the likely source of circulating CRH. In the present study, we examined CRH messenger RNA (mRNA) and peptide expression in fetal membranes and the placenta of 14 pregnant rhesus monkeys (140-161 days gestational age) using Northern blot analysis, in situ hybridization, and immunocytochemistry to define the cellular distribution of CRH during the last third of pregnancy and in relation to onset of both spontaneous term and androstenedione-induced preterm labor. To localize the target tissues for placental CRH, CRH receptor gene expression was also studied in the fetal membranes and placenta. CRH mRNA in the placenta was of similar molecular size to hypothalamic CRH. Placental CRH mRNA increased significantly during both spontaneous term and androstenedione-induced preterm labor (P < 0.05). Placental CRH peptide detected by CRH immunostaining also increased, matching the changes of CRH mRNA. In situ hybridization and immunocytochemistry demonstrated that syncytiotrophoblast cells are the major cell type expressing CRH mRNA and producing CRH protein. CRH mRNA was not detected in either amnion or chorion. CRH receptor complementary DNA and oligo probes that successfully hybridized CRH receptor mRNA in the fetal rhesus monkey hypothalamus failed to reveal the existence of CRH receptor mRNA in amnion, chorion, and placenta by Northern blot hybridization. In conclusion, placental but not fetal membrane syncytiotrophoblasts are the source of CRH production in the pregnant rhesus monkey. The significant increase in CRH peptide and mRNA content in both spontaneous term and androstenedione-induced preterm labor indicates a role for CRH in the process of parturition. The lack of CRH receptor mRNA in either the fetal membranes or the placenta suggests that placental CRH exerts its action at sites other than these tissues.

Corticotropin-releasing hormone and its receptor distribution in fetal membranes and placenta of the rhesus monkey in late gestation and labor.

Maternal plasma corticotropin-Releasing Hormone (CRH) rises from midgestation to term and increases further during labor in pregnant women. The primate placenta contains both the CRH peptide and its gene and is the likely source of circulating CRH. In the present study, we examined CRH messenger RNA (mRNA) and peptide expression in fetal membranes and the placenta of 14 pregnant rhesus monkeys (140-161 days gestational age) using Northern blot analysis, in situ hybridization, and immunocytochemistry to define the cellular distribution of CRH during the last third of pregnancy and in relation to onset of both spontaneous term and androstenedione-induced preterm labor. To localize the target tissues for placental CRH, CRH receptor gene expression was also studied in the fetal membranes and placenta. CRH mRNA in the placenta was of similar molecular size to hypothalamic CRH. Placental CRH mRNA increased significantly during both spontaneous term and androstenedione-induced preterm labor (P < 0.05). Placental CRH peptide detected by CRH immunostaining also increased, matching the changes of CRH mRNA. In situ hybridization and immunocytochemistry demonstrated that syncytiotrophoblast cells are the major cell type expressing CRH mRNA and producing CRH protein. CRH mRNA was not detected in either amnion or chorion. CRH receptor complementary DNA and oligo probes that successfully hybridized CRH receptor mRNA in the fetal rhesus monkey hypothalamus failed to reveal the existence of CRH receptor mRNA in amnion, chorion, and placenta by Northern blot hybridization. In conclusion, placental but not fetal membrane syncytiotrophoblasts are the source of CRH production in the pregnant rhesus monkey. The significant increase in CRH peptide and mRNA content in both spontaneous term and androstenedione-induced preterm labor indicates a role for CRH in the process of parturition. The lack of CRH receptor mRNA in either the fetal membranes or the placenta suggests that placental CRH exerts its action at sites other than these tissues.

Localization of the corticotropin-releasing hormone receptor gene on mouse Chromosome 11

Localization of the corticotropin-releasing hormone receptor gene on mouse Chromosome 11

Localization of corticotropin-releasing hormone (CRH) receptor mRNA in adult rat brain by in situ hybridization histochemistry

Even though functional CRH receptors have been identified in several brain regions by ligand binding, the identity of brain areas expressing the CRH receptor gene has not been described. The recent cloning of the rat CRH receptor gene has permitted us to conduct an in situ hybridization histochemistry study to localize CRH receptor mRNA in brain, using an antisense 35S-labeled riboprobe and autoradiography. In virus- and pathogen-free, unstressed, adult male Sprague-Dawley rats we observed CRH receptor gene expression in several brain regions, most of which had been previously shown to bind radiolabeled CRH. Those regions include the pituitary, olfactory bulb, hippocampal formation, cerebral and cerebellar cortexes, hypothalamus, median eminence, amygdala, olfactory tubercle, choroid plexus, thalamus, and inferior colliculus. Further studies are needed to determine the cell types expressing both CRH receptor mRNA and the CRH receptor peptide in nervous system as well as in peripheral tissues.

Localization of corticotropin-releasing hormone (CRH) receptor mRNA in adult rat brain by in situ hybridization histochemistry.

Even though functional CRH receptors have been identified in several brain regions by ligand binding, the identity of brain areas expressing the CRH receptor gene has not been described. The recent cloning of the rat CRH receptor gene has permitted us to conduct an in situ hybridization histochemistry study to localize CRH receptor mRNA in brain, using an antisense 35S-labeled riboprobe and autoradiography. In virus- and pathogen-free, unstressed, adult male Sprague-Dawley rats we observed CRH receptor gene expression in several brain regions, most of which had been previously shown to bind radiolabeled CRH. Those regions include the pituitary, olfactory bulb, hippocampal formation, cerebral and cerebellar cortexes, hypothalamus, median eminence, amygdala, olfactory tubercle, choroid plexus, thalamus, and inferior colliculus. Further studies are needed to determine the cell types expressing both CRH receptor mRNA and the CRH receptor peptide in nervous system as well as in peripheral tissues.

Human corticotropin-releasing hormone receptor gene (CRHR) is located on the long arm of chromosome 17 (17q12-qter).

Using polymerase chain reaction amplification of commercially available DNA templates, we have mapped the human corticotropin-c releasing hormone receptor gene (CRHR) to the long arm of chromosome 17 (17q12-qter).