Alternative titles; symbols
HGNC Approved Gene Symbol: CRHR1
Cytogenetic location: 17q21.31 Genomic coordinates (GRCh38) : 17:45,784,320-45,835,828 (from NCBI)
The corticotropin-releasing hormone receptor binds to corticotropin-releasing hormone (122560), a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress.
Corticotropin-releasing hormone (CRH; 122560), also called corticotropin-releasing factor (CRF), is a 41-amino acid peptide synthesized in the hypothalamus and capable of stimulating the production of adrenocorticotropic hormone (ACTH) and other proopiomelanocortin (176830) products of the anterior pituitary. Anatomic, functional, and pharmacologic studies have suggested numerous physiologic roles for CRH within the brain, adrenals, gonads, the gastrointestinal tract, placenta, and sites of inflammation. It is the principal neuroregulator of the hypothalamic-pituitary-adrenocortical axis and plays an important role in coordinating the endocrine, autonomic, and behavioral responses to stress and immune challenge. Chen et al. (1993) reported the cloning of a cDNA coding for a CRH receptor from a human corticotropic tumor library. The cloned cDNA encoded a 415-amino acid protein comprising 7 putative membrane-spanning domains. It was structurally related to the calcitonin/vasoactive intestinal peptide/growth hormone-releasing hormone subfamily of G protein-coupled receptors.
Perrin et al. (2001) reported that CRFR1 belongs to the type B 7-transmembrane receptor family and is expressed as multiple splice variants. They found that the N-terminal signal peptide is cleaved from the mature receptor and that the N-terminal extracellular domain has disulfide bonds between cys30 and cys54, cys44 and cys87, and cys68 and cys102.
While CRFR1 shares 70% sequence identity with CRFR2 (602034), it has much higher affinity for rat/human CRF. Liaw et al. (1997) determined the regions involved in receptor-ligand binding and/or receptor activation using chimeric receptor constructs of human CRFR1 and CRFR2 and generated point mutations of both receptors. The EC(50) values in stimulation of intracellular cAMP by the receptors for the peptide ligand were determined using a cAMP-dependent reporter system. Three regions of the receptor were found to be important for optimal binding of CRF and/or receptor activation. The first region was mapped to the junction of the third extracellular domain and the fifth transmembrane domain. Substitutions of 3 amino acids of CRFR1 in this region (val266, tyr267, and thr268) by the corresponding CRFR2 amino acids (asp266, leu267, and val268) increased the EC(50) value by approximately 10-fold. The other 2 regions were in the second extracellular domain of the CRFR1 (amino acids 175-178 and his189). Substitutions in each of these 2 regions increased the EC(50) value for CRF by approximately 7- to 8-fold, but only in the presence of the amino acid 266-268 mutation involving the first region, suggesting that the latter 2 regions may play a secondary role in peptide ligand binding.
Asakura et al. (1997) found that the thecal compartment of the human ovary contains a CRF system endowed with CRF, CRFR1, and CRFBP 122559.
Grammatopoulos et al. (1998) studied the expression of CRHR1 in human myometrium. They used RT-PCR, fluorescence in situ hybridization, and immunofluorescence to identify and localize the 4 subtypes, 1-alpha, 1-beta, 2-alpha, and the variant C, of CRHR1. The CRHR1 subtypes in myometrium exhibited differential expression patterns; in human pregnant myometrium at term, all 4 receptor subtypes were expressed, whereas only the 1-alpha and 1-beta receptor subtypes were found in the nonpregnant myometrium. The authors concluded that CRHR1 acting via different receptor subtypes is able to exert different actions on the myometrium in the pregnant state compared to the nonpregnant state. Furthermore, in the pregnant human uterus, receptors were localized in both smooth muscle and fibroblasts, suggesting that CRHR1 expression plays an important modulatory role in myometrial and possibly in cervical function.
Leproult et al. (2001) examined the effects of bright light on the profiles of hormones known to be affected by sleep deprivation (TSH; see 188540) or involved in behavioral activation (cortisol). The early morning transition from dim to bright light suppressed melatonin secretion, induced an immediate, greater than 50% elevation of cortisol levels, and limited the deterioration of alertness normally associated with overnight sleep deprivation. No effect was detected on TSH profiles. The authors concluded that these data unambiguously demonstrate an effect of light on the corticotropic axis that is dependent on time of day.
Perrin et al. (2001) expressed the isolated soluble N-terminal extracellular domain of CRFR1 in E. coli and COX-M6 cells and found that 2 of 3 disulfide bonds in CRFR1 were required for binding the CRF antagonist astressin.
Karteris et al. (2003) investigated the expression of CRHR1 levels in placentas from women who had undergone normal deliveries (control group) and patients who had been diagnosed as having preeclampsia or intrauterine growth retardation (IUGR). Results showed that placental CRHR1 mRNA levels (as shown by quantitative RT-PCR) and protein levels (shown by Western blotting analysis) were significantly (P less than 0.05) reduced in all of the complicated pregnancies. The authors concluded that these findings might suggest that changes in receptor expression may contribute toward dysregulation of the dynamic balance controlling vascular resistance.
CRF and its family members are implicated in stress-related disorders such as anxiety and depression. In mice, Nie et al. (2004) found that CRF and ethanol enhanced inhibitory GABAergic neurotransmission in central amygdala neurons from wildtype and Crfr2 knockout mice, but not Crfr1 knockout mice. Crfr1 antagonists blocked both CRF and ethanol effects in wildtype mice. These data indicated that the CRF1 receptors mediate ethanol enhancement of GABAergic synaptic transmission in the central amygdala, and suggested a cellular mechanism underlying involvement of CRF in ethanol's behavioral and motivational effects.
Refojo et al. (2011) determined that CRHR1 is expressed in forebrain glutamatergic and GABAergic neurons as well as in midbrain dopaminergic neurons. Via specific CRHR1 deletions in glutamatergic, GABAergic, dopaminergic, and serotonergic cells, they found that the lack of CRHR1 in forebrain glutamatergic circuits reduced anxiety and impaired neurotransmission in the amygdala and hippocampus. Selective deletion of CRHR1 in midbrain dopaminergic neurons increased anxiety-like behavior and reduced dopamine release in the prefrontal cortex. Refojo et al. (2011) concluded that their results defined a bidirectional model for the role of CRHR1 in anxiety and suggested that an imbalance between CRHR1-controlled anxiogenic glutamatergic and anxiolytic dopaminergic systems may lead to emotional disorders.
Lemos et al. (2012) reported that corticotropin-releasing factor (CRF; 122560), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2 (602034). Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Lemos et al. (2012) concluded that their results offer a biologic substrate for the switch in affect which is central to stress-induced depressive disorders.
Using overexpression and knockdown studies, Wang et al. (2013) found that acute social defeat stress in young adult male mice impaired cognition via Crhr1-dependent downregulation of the cell adhesion molecule nectin-3 (PVRL3; 607147) in hippocampus. Stress, upregulation of hippocampal Crhr1, or knockdown of nectin-3 also reduced spine density in CA3, dentate gyrus, and CA1 principal neurons. Overexpression of nectin-3 reversed the effects of stress or Crhr1 overexpression on spine loss and cognitive performance.
Sakai et al. (1998) determined that the CRHR1 gene contains at least 14 exons spanning 20 kb of genomic DNA. The CRHR1 isoforms appear to originate from the same gene by alternative splicing. The isoform with the highest CRF affinity and the ability to transduce the most cAMP accumulation in response to CRF binding is encoded by 13 exons and excludes exon 6.
Using PCR in the analysis of somatic cell hybrids, Polymeropoulos et al. (1995) mapped the CRHR gene to chromosome 17 and sublocalized it to 17q12-q22 by study of a regional somatic cell hybrid panel.
Crystal Structure
Hollenstein et al. (2013) reported the crystal structure of the transmembrane domain of human CRHR1 in complex with a small molecule antagonist. The structure provides detailed insight into the architecture of class B receptors. Hollenstein et al. (2013) described atomic details of the interactions of the receptor with the nonpeptide ligand that binds deep within the receptor.
Dieterich et al. (1998) investigated a possible role of CRHR1 in the pathogenesis of Cushing disease (219080). ACTH-secreting pituitary adenomas and nonsecreting pituitary adenomas were analyzed for mutations in the CRHR1 gene by PCR and sequencing. They found no mutations affecting the CRHR1 protein, but did find a significant overexpression of CRHR1 mRNA in ACTH-secreting pituitary adenomas versus inactive adenomas and normal pituitaries. The authors concluded that mutations of the CRHR1 gene are unlikely to be involved in Cushing disease and that the observed overexpression of the CRHR1 mRNA may be related to disturbed receptor regulation in ACTH-secreting pituitary adenomas.
Tantisira et al. (2004) investigated the genetic contribution to the variation in response to inhaled corticosteroid therapy in asthma (600807). Variation in CRHR1 was associated with enhanced response to therapy in each of 3 clinical trial populations. Individuals homozygous for the variants of interest manifested a doubling to quadrupling of the lung function response to corticosteroids compared with those lacking the variants (P values ranging from 0.006 to 0.025).
Timpl et al. (1998) showed that in mice in whom the Crhr1 gene had been disrupted, the medulla of the adrenal gland is atrophied and stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced. The homozygous mutants exhibited increased exploratory activity and reduced anxiety-related behavior under both basal conditions and following alcohol withdrawal. The results demonstrated a key role of the Crhr1 receptor in mediating the stress response and anxiety-related behavior. CRH had been previously identified as a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress and had been implicated in the stress-like and other adverse consequences of drug abuse, such as withdrawal from alcohol. Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala, and cerebellum, and activation of this receptor stimulates adenylate cyclase.
Smith et al. (1998) generated mice lacking Crhr1 by homologous recombination. They noted markedly reduced anxiety in these mice, as well as disruption of the hypothalamic-pituitary-adrenal (HPA) axis. The mice had low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. This agenesis could be rescued by ACTH replacement. Offspring from homozygote crosses died within 2 days after birth due to a pronounced lung dysplasia. Smith et al. (1998) concluded that CRHR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.
Sillaber et al. (2002) studied Crhr1 -/- mice generated by Timpl et al. (1998). In homozygous mutant mice, stress leads to enhanced and progressively increasing alcohol intake. The effect of repeated stress on alcohol drinking behavior appeared with a delay and persisted throughout life. It was associated with an upregulation of the N-methyl-D-aspartate receptor subunit NR2B (138252). Sillaber et al. (2002) concluded that alterations in the CRHR1 gene and adaptional changes in NR2B subunits may constitute a genetic risk factor for stress-induced alcohol drinking and alcoholism.
Yoshida-Hiroi et al. (2002) studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides, and the ultrastructure of chromaffin cells in Crhr1-deficient mice. They also examined whether treatment of Crhr1-null mice with ACTH could restore function to the adrenal medulla. ACTH treatment increased epinephrine and phenylethanolamine N-methyltransferase mRNA levels in the mice but failed to restore them to normal levels. Proenkephalin mRNA levels in both saline- and ACTH-treated Crhr1 null mice were higher than in control animals (P less than 0.05, P less than 0.01, respectively) although expression of neuropeptide Y and chromogranin B did not differ. Ultrastructurally, chromaffin cells in saline-treated mice had a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. Yoshida-Hiroi et al. (2002) concluded that CRHR1 is required for normal chromaffin cell structure and function and epinephrine biosynthesis.
Muller et al. (2003) generated a Crhr1 conditional knockout mouse line in which Camk2a-driven, cre-mediated inactivation of Crhr1 occurred in limbic structures, including the hippocampus and amygdala, but not in the pituitary gland, leaving the hypothalamic-pituitary-adrenocortical (HPA) system intact. These conditional mutant mice showed reduced anxiety with normal basal HPA system activity. In addition, Muller et al. (2003) provided evidence that limbic Crhr1 is required for proper feedback control of the HPA system and hormonal adaptation to stress. Muller et al. (2003) concluded that limbic Crhr1 modulates anxiety-related behavior independent of HPA system function, and may play a role in certain psychiatric disorders.
Contarino and Papaleo (2005) found that Crhr1 +/- and Crhr1 -/- mice demonstrated significantly less negative affective states of opiate withdrawal compared to wildtype mice. Opiate withdrawal elevated dynorphin (see PDYN; 131340) mRNA levels in the nucleus accumbens of wildtype mice, but not of Crhr1 +/- or -/- mice. The findings suggested a critical role for CRH/CRHR1 pathways in opiate dependence and withdrawal.
Papaleo et al. (2007) found that Crhr1-null mice undergoing opiate withdrawal developed more severe and prolonged somatic withdrawal symptoms, including increased jumps, 'wet-dog' shakes, and diarrhea, compared to control mice. In mutant mice, this was associated with decreased Crh expression and increased dynorphin expression in the paraventricular nucleus of the hypothalamus, which was aberrant compared to controls. Treatment with low levels of corticosterone reduced the exaggerated somatic withdrawal symptoms and restored more normal Crh and dynorphin expression patterns in the paraventricular nucleus of the hypothalamus, and restored dynorphin levels in the striatum. Similar results were obtained with pharmacologic disruption of the Crh/Crhr1 pathway. The findings implicated a role for both the HPA axis and the extrahypothalamic Crh/Crhr1 receptor circuitry in somatic, molecular, and endocrine alterations induced by opiate withdrawal.
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