Disease relevance of CRHR1

• Patients with obesity and metabolic syndrome who often have subtle, but chronic hypothalamic-pituitary-adrenal hyperactivity, which may reflect central dysregulation of CRH and consequently glucocorticoid hypersecretion, could possibly be treated by administration of CRHR1 antagonists [1].
• METHODS: Immunohistochemical analysis was used to confirm enhanced expression of specific CRH receptor subtypes in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) synovium [2].
• These results implicate CRH-R in chronic urticaria, which is often exacerbated by stress [3].
• These data clearly demonstrate that non-peptide CRF1 receptor antagonists, when administered systemically, can specifically block central CRF1 receptors and provide tools that can be used to determine the role of CRF1 receptors in various neuropsychiatric and neurodegenerative disorders [4].
• These findings lend support to the hypothesis that hyperactivation of CRF1 receptors may contribute to the co-morbidity of anxiety and depression and irritable bowel syndrome [5].

Psychiatry related information on CRHR1

• Recently novel non-peptidic antagonists directed against CRH-R1 or CRH-R2 have been proposed as promising agents in the treatment of depression, anxiety and eating disorder [6].
• This is the first time that an association of CRHR1 with specific patterns of alcohol consumption has been reported [7].
• A large body of preclinical and clinical evidence points to a key role of the corticotropin-releasing hormone (CRH) receptor 1 subtype (CRHR1) in mediating CRH-elicited effects in anxiety, depressive disorders and stress-associated pathologies [8].
• Non-peptide CRF1 antagonists have been recently synthesized for the treatment of CNS related diseases, such as anxiety, depression and drug abuse [9].
• The development of selective CRF-receptor antagonists will permit direct testing of the hypothesis that CRF hypersecretion is responsible for certain of the cardinal features of affective and anxiety disorders [10].

High impact information on CRHR1

• The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism [11].
• Two types of mammal CRH-R exist, CRH-R1 and CRH-R2, each with unique splicing patterns and remarkably distinct pharmacological properties, but similar signaling properties, probably reflecting their distinct and sometimes contrasting biological functions [12].
• The CRH receptor (CRH-R) is a member of the secretin family of G protein-coupled receptors [12].
• This report was prepared by the International Union of Pharmacology Subcommittee on CRF Receptors, to summarize the current state of CRF receptor biology and to propose changes in the classification and nomenclature of CRF ligands and receptors [13].
• In contrast with the V3 receptor, CRH receptor mRNA was detected in the majority of neuroendocrine tumors irrespective of their POMC status [14].

Chemical compound and disease context of CRHR1

• We conclude that even though 8-week antagonism of CRHR1 by the non-peptide antalarmin blunts basal concentrations of ACTH and corticosterone, and affects the adrenal responsiveness to ACTH, it does not blunt the HPA response to acute stress, and it does not appear to cause stress-induced adrenal insufficiency [15].
• OT action was mediated via pertussis toxin-sensitive G proteins, which directly inhibit adenylate cyclase and, via activation of protein kinase C, phosphorylate the CRH receptor, leading to desensitization [16].
• The increases also depended on extracellular Ca2+ and were blocked by Cd2+, Co2+, verapamil, and nifedipine. alpha-Helical CRF-(9-41), a synthetic CRF receptor antagonist, and pertussis toxin also blocked the increase in [Ca2+]i induced by the two peptides [17].
• Ectopic ACTH Cushing's syndrome: V3 vasopressin receptor but not CRH receptor gene expression in a pulmonary carcinoid tumor [18].
• Rats were divided into four groups according to diet as follows: 100 mg/kg body weight OPZ group, 100 mg/kg body weight OPZ and 30 mg/kg body weight rebamipide (OPZ + trebanipide group), 30 mg/kg body weight rebamipide, and normal diet (CRF-1) [19].

Biological context of CRHR1

• Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment [20].
• These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated [20].
• In those with lower-anxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D [20].
• The study shows that the upstream AUG in 5'-UTR of CRHR1 mRNA inhibits receptor expression by inhibiting mRNA translation and suggests the short open reading frame in the 5'-UTR plays a role in regulating translation of the CRH receptor [21].
• Moreover, systemic administration of antalarmin, a nonpeptide CRHR1 antagonist, prevented vascular permeability only by CRH and not by compound 48/80 or SP [22].

Anatomical context of CRHR1

• CRHR1 was also identified in cultured leukemic human mast cells using RT-PCR [22].
• Western blot analysis of CRHR1 protein in pituitary membranes from adrenalectomized rats showed unchanged receptor mRNA levels and increased CRHR1 protein, despite binding down-regulation, suggesting that decreased binding is due to homologous desensitization, rather than reduced receptor synthesis [23].
• In order to decrease CRH signaling, many pharmaceutical companies have developed small molecules that after oral ingestion, penetrate the blood-brain barrier and selectively bind at CRHR1 with high affinity [24].
• In addition, CRH receptor expression was examined in isolated synovial endothelial cells and synoviocytes [2].
• To further elucidate the biologic role of CRH at peripheral sites, we examined the expression of known CRH receptor subtypes in inflamed human synovium and compared the expression patterns in normal synovium [2].

Associations of CRHR1 with chemical compounds

• We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks [20].
• Female rats treated with the non-peptidic CRH receptor 1 (CRHR1) specific antagonist antalarmin, in the first 6 days of gestation, have undergone a decrease of endometrial implantation sites and live embryos and markedly diminished endometrial FasL expression [25].
• The parallel increases in intensity of CRF, CRF-R1, and 17 alpha-hydroxylase messenger ribonucleic acid (mRNA) and proteins in thecal cells with follicular maturation suggest that the intraovarian CRF system may play an autocrine role regulating androgen biosynthesis, with a downstream effect on estrogen production by granulosa cells [26].
• The parallel increases in intensity of CRF, CRF-R1, and 17 alpha-hydroxylase proteins and gene expression with follicular maturation suggest that the intraovarian CRF system may play an autocrine role in androgen biosynthesis with a downstream effect on estrogen production by the granulosa cells [27].
• In cyclic AMP stimulation and CRF-binding assays, it was established that different extracellular regions of CRFR1 and CRFR2 conferred their ligand selectivities [28].

Physical interactions of CRHR1

• In conclusion, it appears that a complex intraadrenal CRF-UCN/CRF-receptor system exists in both human and rat adrenals controlling catecholamine secretion and synthesis [29].
• Radioimmunoassay indicated that CRH binds to CRH receptor in HSC-2 cell when activating the metabolic pathway [30].

Regulatory relationships of CRHR1

• CRH down-regulated CRH-R1 and CRH-R2 mRNA expression in isolated adipocytes [31].
• CONCLUSIONS: CRH, Unc, and ACTH stimulate all elements of the DHEAS synthetic pathway and activate CRH-R1 as well [32].
• However, in human chromaffin cells, activation of CRF1 receptors induced tyrosine hydroxylase, whereas activation of CRF2 suppressed it [29].
• Since the first cytoplasmic loop is highly conserved in all the members of the hCRF receptor family we have examined whether the presence of the 29 amino acid cassette in CRF-RII influences G protein coupling in LLCPK-1 cells stably expressing the type I and type II hCRF receptors [33].
• RNase protection assays carried out on MCF7 under basal conditions showed that these cells express in a constitutive manner the CRH-R1 receptor subtype [34].

Other interactions of CRHR1

• Corticotropin-releasing hormone signaling in synovial tissue from patients with early inflammatory arthritis is mediated by the type 1 alpha corticotropin-releasing hormone receptor [2].
• There are three receptors, CRF1, CRF2 alpha and CRF2 beta, which encode 411, 415 and 431 amino acid proteins and transduce signals via the stimulation of intracellular cAMP production [35].
• Both CRF and UCN 1 effects were attenuated by astressin, a non-selective CRF receptor antagonist [36].
• CRF-BP has differential affinities for CRF receptor antagonists, binding alpha-helical CRF-(9-41) with high affinity and [D-Phe12, Nle21,38]hCRF-(12-41) with low affinity [37].
• Using RT-PCR and fluorescent in situ hybridization, we demonstrated that UCN II and type-2 CRH receptor (CRH-R2) mRNAs were expressed in human nonpregnant and pregnant myometrium [38].

Analytical, diagnostic and therapeutic context of CRHR1

• In vitro translation of luciferase or CRHR constructs with or without mutation of the upstream ATG, and Western blot analysis with anti-luciferase and anti-CRHR1 antibodies confirmed that mutation of the upstream ATG increases translation of the main ORF [21].
• While clinical trials of R-121919 have been discontinued after phase IIa studies, a number of other CRHR1 antagonists are being developed, and hopefully this advance will ultimately lead to a favorable alternative to currently available antidepressant drugs [24].
• Immunofluorescence double-labeling was used to further characterize CRH receptor-expressing cells [2].
• Therefore, we employed quantitative TaqMan PCR to analyze the expression and distribution of both CRH-R1 and CRH-R2 in human brain tissue and peripheral organs [6].
• Because a lack of CRH type 1 receptors (CRH-R1) on the chicken thyrotropes has been previously reported, two hypotheses were tested using in situ hybridization and perifusion studies: 1) TSH secretion might be induced in a paracrine way involving melanocortins from the corticotropes; and 2) thyrotropes might express another type of CRH-R [39].

References