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Gene Review

CRHR1  -  corticotropin releasing hormone receptor 1

Homo sapiens

Synonyms: CRF-R, CRF-R-1, CRF-R1, CRF1, CRFR, ...
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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


Biological context of CRHR1


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


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].


  1. Nonpeptide corticotropin-releasing hormone receptor type 1 antagonists and their applications in psychosomatic disorders. Contoreggi, C., Rice, K.C., Chrousos, G. Neuroendocrinology (2004) [Pubmed]
  2. Corticotropin-releasing hormone signaling in synovial tissue from patients with early inflammatory arthritis is mediated by the type 1 alpha corticotropin-releasing hormone receptor. McEvoy, A.N., Bresnihan, B., FitzGerald, O., Murphy, E.P. Arthritis Rheum. (2001) [Pubmed]
  3. Corticotropin-releasing hormone receptor-1 and histidine decarboxylase expression in chronic urticaria. Papadopoulou, N., Kalogeromitros, D., Staurianeas, N.G., Tiblalexi, D., Theoharides, T.C. J. Invest. Dermatol. (2005) [Pubmed]
  4. Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications. McCarthy, J.R., Heinrichs, S.C., Grigoriadis, D.E. Curr. Pharm. Des. (1999) [Pubmed]
  5. Role of corticotropin releasing factor receptor subtype 1 in stress-related functional colonic alterations: implications in irritable bowel syndrome. Taché, Y., Martinez, V., Million, M., Maillot, C. The European journal of surgery. Supplement. : = Acta chirurgica. Supplement. (2002) [Pubmed]
  6. Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls. Hiroi, N., Wong, M.L., Licinio, J., Park, C., Young, M., Gold, P.W., Chrousos, G.P., Bornstein, S.R. Mol. Psychiatry (2001) [Pubmed]
  7. Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples. Treutlein, J., Kissling, C., Frank, J., Wiemann, S., Dong, L., Depner, M., Saam, C., Lascorz, J., Soyka, M., Preuss, U.W., Rujescu, D., Skowronek, M.H., Rietschel, M., Spanagel, R., Heinz, A., Laucht, M., Mann, K., Schumann, G. Mol. Psychiatry (2006) [Pubmed]
  8. Getting closer to affective disorders: the role of CRH receptor systems. Müller, M.B., Wurst, W. Trends in molecular medicine. (2004) [Pubmed]
  9. The corticotropin-releasing factor (CRF) family of neuropeptides in inflammation: potential therapeutic applications. Gravanis, A., Margioris, A.N. Current medicinal chemistry. (2005) [Pubmed]
  10. New vistas in neuropeptide research in neuropsychiatry: focus on corticotropin-releasing factor. Nemeroff, C.B. Neuropsychopharmacology (1992) [Pubmed]
  11. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Koolen, D.A., Vissers, L.E., Pfundt, R., de Leeuw, N., Knight, S.J., Regan, R., Kooy, R.F., Reyniers, E., Romano, C., Fichera, M., Schinzel, A., Baumer, A., Anderlid, B.M., Schoumans, J., Knoers, N.V., van Kessel, A.G., Sistermans, E.A., Veltman, J.A., Brunner, H.G., de Vries, B.B. Nat. Genet. (2006) [Pubmed]
  12. The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Hillhouse, E.W., Grammatopoulos, D.K. Endocr. Rev. (2006) [Pubmed]
  13. International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands. Hauger, R.L., Grigoriadis, D.E., Dallman, M.F., Plotsky, P.M., Vale, W.W., Dautzenberg, F.M. Pharmacol. Rev. (2003) [Pubmed]
  14. The pituitary V3 vasopressin receptor and the corticotroph phenotype in ectopic ACTH syndrome. de Keyzer, Y., Lenne, F., Auzan, C., Jégou, S., René, P., Vaudry, H., Kuhn, J.M., Luton, J.P., Clauser, E., Bertagna, X. J. Clin. Invest. (1996) [Pubmed]
  15. Chronic administration of the non-peptide CRH type 1 receptor antagonist antalarmin does not blunt hypothalamic-pituitary-adrenal axis responses to acute immobilization stress. Wong, M.L., Webster, E.L., Spokes, H., Phu, P., Ehrhart-Bornstein, M., Bornstein, S., Park, C.S., Rice, K.C., Chrousos, G.P., Licinio, J., Gold, P.W. Life Sci. (1999) [Pubmed]
  16. Activation of protein kinase C by oxytocin inhibits the biological activity of the human myometrial corticotropin-releasing hormone receptor at term. Grammatopoulos, D.K., Hillhouse, E.W. Endocrinology (1999) [Pubmed]
  17. Mystixin-7 and mystixin-11 increase cytosolic free Ca2+ and inositol trisphosphates in human A-431 cells. Kiang, J.G. Eur. J. Pharmacol. (1995) [Pubmed]
  18. Ectopic ACTH Cushing's syndrome: V3 vasopressin receptor but not CRH receptor gene expression in a pulmonary carcinoid tumor. Chabot, V., de Keyzer, Y., Gebhard, S., Uské, A., Bischof-Delaloye, A., Rey, F., Dusmet, M., Gomez, F. Horm. Res. (1998) [Pubmed]
  19. Rebamipide contributes to reducing adverse effects of long-term administration of omeprazole in rats. Hagiwara, T., Mukaisho, K., Ling, Z.Q., Sakano, T., Sugihara, H., Hattori, T. Dig. Dis. Sci. (2007) [Pubmed]
  20. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Licinio, J., O'Kirwan, F., Irizarry, K., Merriman, B., Thakur, S., Jepson, R., Lake, S., Tantisira, K.G., Weiss, S.T., Wong, M.L. Mol. Psychiatry (2004) [Pubmed]
  21. Inhibition of corticotropin releasing hormone type-1 receptor translation by an upstream AUG triplet in the 5' untranslated region. Xu, G., Rabadan-Diehl, C., Nikodemova, M., Wynn, P., Spiess, J., Aguilera, G. Mol. Pharmacol. (2001) [Pubmed]
  22. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its proinflammatory effects. Theoharides, T.C., Singh, L.K., Boucher, W., Pang, X., Letourneau, R., Webster, E., Chrousos, G. Endocrinology (1998) [Pubmed]
  23. Corticotropin releasing hormone receptors: two decades later. Aguilera, G., Nikodemova, M., Wynn, P.C., Catt, K.J. Peptides (2004) [Pubmed]
  24. Corticotropin-releasing hormone modulators and depression. Holsboer, F. Current opinion in investigational drugs (London, England : 2000) (2003) [Pubmed]
  25. Participation of maternal and fetal CRH in early phases of human implantation: the role of antalarmin. Makrigiannakis, A., Zoumakis, E., Kalantaridou, S., Chrousos, G., Gravanis, A. Curr. Drug Targets Immune Endocr. Metabol. Disord. (2004) [Pubmed]
  26. Corticotropin-releasing factor inhibits luteinizing hormone-stimulated P450c17 gene expression and androgen production by isolated thecal cells of human ovarian follicles. Erden, H.F., Zwain, I.H., Asakura, H., Yen, S.S. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  27. Expression of genes encoding corticotropin-releasing factor (CRF), type 1 CRF receptor, and CRF-binding protein and localization of the gene products in the human ovary. Asakura, H., Zwain, I.H., Yen, S.S. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  28. The ligand-selective domains of corticotropin-releasing factor type 1 and type 2 receptor reside in different extracellular domains: generation of chimeric receptors with a novel ligand-selective profile. Dautzenberg, F.M., Kilpatrick, G.J., Wille, S., Hauger, R.L. J. Neurochem. (1999) [Pubmed]
  29. Corticotropin-releasing factor (CRF) and the urocortins differentially regulate catecholamine secretion in human and rat adrenals, in a CRF receptor type-specific manner. Dermitzaki, E., Tsatsanis, C., Minas, V., Chatzaki, E., Charalampopoulos, I., Venihaki, M., Androulidaki, A., Lambropoulou, M., Spiess, J., Michalodimitrakis, E., Gravanis, A., Margioris, A.N. Endocrinology (2007) [Pubmed]
  30. Corticotropin releasing hormone stimulates proliferation of keratinocytes. Mitsuma, T., Matsumoto, Y., Tomita, Y. Life Sci. (2001) [Pubmed]
  31. Corticotropin-releasing hormone system in human adipose tissue. Seres, J., Bornstein, S.R., Seres, P., Willenberg, H.S., Schulte, K.M., Scherbaum, W.A., Ehrhart-Bornstein, M. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  32. Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells. Sirianni, R., Mayhew, B.A., Carr, B.R., Parker, C.R., Rainey, W.E. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  33. The alternatively spliced type II corticotropin-releasing factor receptor, stably expressed in LLCPK-1 cells, is not well coupled to the G protein(s). Nabhan, C., Xiong, Y., Xie, L.Y., Abou-Samra, A.B. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  34. Evidence that corticotropin-releasing hormone inhibits cell growth of human breast cancer cells via the activation of CRH-R1 receptor subtype. Graziani, G., Tentori, L., Muzi, A., Vergati, M., Tringali, G., Pozzoli, G., Navarra, P. Mol. Cell. Endocrinol. (2007) [Pubmed]
  35. Neurobiology of corticotropin releasing factor (CRF) receptors and CRF-binding protein: implications for the treatment of CNS disorders. Behan, D.P., Grigoriadis, D.E., Lovenberg, T., Chalmers, D., Heinrichs, S., Liaw, C., De Souza, E.B. Mol. Psychiatry (1996) [Pubmed]
  36. Modulation of Ca2+ influx by corticotropin-releasing factor (CRF) family of peptides via CRF receptors in rat pancreatic beta-cells. Kageyama, K., Kimura, R., Suga, S., Ogawa, Y., Suda, T., Wakui, M. Peptides (2006) [Pubmed]
  37. Ligand requirements of the human corticotropin-releasing factor-binding protein. Sutton, S.W., Behan, D.P., Lahrichi, S.L., Kaiser, R., Corrigan, A., Lowry, P., Potter, E., Perrin, M.H., Rivier, J., Vale, W.W. Endocrinology (1995) [Pubmed]
  38. Urocortin II is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation: potential role of the type-2 corticotropin-releasing hormone receptor in the control of myometrial contractility. Karteris, E., Hillhouse, E.W., Grammatopoulos, D. Endocrinology (2004) [Pubmed]
  39. Corticotropin-releasing hormone (CRH)-induced thyrotropin release is directly mediated through CRH receptor type 2 on thyrotropes. De Groef, B., Goris, N., Arckens, L., Kuhn, E.R., Darras, V.M. Endocrinology (2003) [Pubmed]
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