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Gene Review

CRHR2  -  corticotropin releasing hormone receptor 2

Homo sapiens

Synonyms: CRF-R-2, CRF-R2, CRF-RB, CRF2, CRF2R, ...
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Disease relevance of CRHR2


Psychiatry related information on CRHR2

  • The purpose of the present study was to investigate the association between the CRHR2 gene and personality traits, evaluated using the Revised NEO Personality Inventory (NEO PI-R), in 243 healthy Japanese subjects [5].
  • Abnormal signaling at corticotropin-releasing factor CRF1 and CRF2 receptors might contribute to the pathophysiology of stress-related disorders such as anxiety, depression and eating disorders, in addition to cardiac and inflammatory disorders [6].
  • These limbic nuclei are reciprocally innervated, are involved in stress and affective disorders, and have high densities of the CRF receptors CRF1 and CRF2 [7].
  • Although both neurobiology and chromosomal location point to the CHRH2 receptor gene as a candidate for panic disorder, our study indicates that the CRHR2 polymorphisms examined do not confer susceptibility to panic disorder [8].

High impact information on CRHR2

  • Tissue distribution analysis of the mRNAs by reverse transcriptase-PCR shows CRF2 receptor mRNA is present in rat brain and detectable in lung and heart [9].
  • In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC [10].
  • Moreover, treatment of HT-29 cells with UcnII, which binds exclusively to CRHR2, stimulated expression of IL-8 and monocyte chemoattractant protein 1 [1].
  • The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist astressin 2B [11].
  • In all samples of inflamed synovium studied, CRH-R1alpha mRNA was detected; however, we were unable to identify CRH-R1beta or any CRH-R2 isoforms in samples from the same cohort of, patients [12].

Biological context of CRHR2

  • More clearly, CRH2 alpha is involved in the CRH effects on food intake [13].
  • The gene coding for human CRF2 receptor consists of at least 12 exons and spans approximately 30 kilobases [14].
  • The cDNA sequence in the protein-coding region is 94% identical to that of the reported rat CRF2 alpha receptor [14].
  • Human CRF2 alpha and beta splice variants: pharmacological characterization using radioligand binding and a luciferase gene expression assay [15].
  • The data suggest that down-regulation of CRF2 receptors selectively attenuates CRF- and UCN-induced anorexia and hypothalamo-pituitary-adrenocortical activation in rats [16].

Anatomical context of CRHR2

  • We expressed the human CRF1 and CRF2 receptor subtypes in stable cell lines and characterized 125I-Tyr0-sauvagine, a high affinity radiolabel suitable for the pharmacological and functional profiles of these proteins [17].
  • The rat esophagus shares some cellular features with skin squamous epithelium and striated muscle that express high levels of corticotropin-releasing factor type 2 (CRF2) receptors or their cognate ligand urocortin (Ucn) 1, 2, and 3 [18].
  • CRF2b wild-type transcript was predominantly expressed in the esophagus, and in addition, several new CRF2 splice variants including six CRF2a isoforms were identified [18].
  • Exposure of dispersed human and rat adrenal chromaffin cells to CRF1 receptor agonists induced catecholamine secretion in a dose-dependent manner, an effect peaking at 30 min, whereas CRF2 receptor agonists suppressed catecholamine secretion [19].
  • We investigated the expression and cell signaling of CRF2 receptors and ligands in the rat esophagus and lower esophageal sphincter (LES) by RT-PCR and quantitative PCR in normal and corticosterone-treated whole esophageal tissue, laser capture microdissected layers, and isolated esophageal cells [18].

Associations of CRHR2 with chemical compounds

  • 125I-Tyr0-sauvagine binding to human CRF2 alpha receptors is saturable and of high affinity (KD = 100-300 PM) and demonstrates guanine nucleotide sensitivity typical of agonist binding to receptors [17].
  • Septal administration of the relatively selective CRF2 antagonist astressin-2B, but not the CRF1-selective antagonist antalarmin, blocked the anxiogenic effects of urocortin 2 [20].
  • Analysis of specific amino acid residues in the N-terminus and C-terminus demonstrated that the presence of a proline at position 11 and alanine at positions 35 and 39 (hCRF numbering) decreases CRF1R activity and increases CRF2R selectivity in CRF, UCN1 and sauvagine peptides [21].
  • Therefore, it is thought that Ucn II may modulate CRF and vasopressin synthesis in the PVN in a paracrine or autocrine fashion through PVN CRF2 receptor [3].
  • In this study, the neuroanatomic distribution of CRF1 and CRF2 receptor binding sites in rhesus monkey (Macaca mulatta) was assessed by using iodine 125 ([125I)-Tyr0]-sauvagine with or without the selective CRF1 receptor antagonist CP-154,526-1 [22].
  • Both CRHR1 and CRHR2 were able to mediate the ligand-induced increase of cAMP production, suggesting that the overexpressed receptors were biologically active [23].

Physical interactions of CRHR2


Regulatory relationships of CRHR2

  • The peptide antagonist alpha-helical CRF(9-41) exhibited a non-competitive antagonism of urocortin-stimulated luciferase expression with both hCRF2 receptor isoforms [15].
  • In rat chromaffin and PC12 cells, CRF1 and CRF2 agonists induced catecholamine synthesis via tyrosine hydroxylase [19].
  • Treatment of primary human myometrial cells with UCN II to specifically activate CRH-R2 resulted in a dose-dependent increase of myosin light chain (MLC(20)) phosphorylation [25].
  • They also raise the possibility that up-regulation of CRF-R2 may contribute to the sensitising influence of E2 on CRF- and stress-induced suppression of the GnRH pulse generator [26].

Other interactions of CRHR2


Analytical, diagnostic and therapeutic context of CRHR2


  1. Corticotropin-releasing hormone receptor 2-deficient mice have reduced intestinal inflammatory responses. Kokkotou, E., Torres, D., Moss, A.C., O'Brien, M., Grigoriadis, D.E., Karalis, K., Pothoulakis, C. J. Immunol. (2006) [Pubmed]
  2. Peripheral urocortin delays gastric emptying: role of CRF receptor 2. Nozu, T., Martinez, V., Rivier, J., Taché, Y. Am. J. Physiol. (1999) [Pubmed]
  3. Urocortins and corticotropin releasing factor type 2 receptors in the hypothalamus and the cardiovascular system. Hashimoto, K., Nishiyama, M., Tanaka, Y., Noguchi, T., Asaba, K., Hossein, P.N., Nishioka, T., Makino, S. Peptides (2004) [Pubmed]
  4. Selective impairment of corticotropin-releasing factor1 (CRF1) receptor-mediated function using CRF coupled to saporin. Maciejewski-Lenoir, D., Heinrichs, S.C., Liu, X.J., Ling, N., Tucker, A., Xie, Q., Lappi, D.A., Grigoriadis, D.E. Endocrinology (2000) [Pubmed]
  5. Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits. Tochigi, M., Kato, C., Otowa, T., Hibino, H., Marui, T., Ohtani, T., Umekage, T., Kato, N., Sasaki, T. Psychiatry Clin. Neurosci. (2006) [Pubmed]
  6. The CRF peptide family and their receptors: yet more partners discovered. Dautzenberg, F.M., Hauger, R.L. Trends Pharmacol. Sci. (2002) [Pubmed]
  7. Corticotropin-releasing factor and Urocortin I modulate excitatory glutamatergic synaptic transmission. Liu, J., Yu, B., Neugebauer, V., Grigoriadis, D.E., Rivier, J., Vale, W.W., Shinnick-Gallagher, P., Gallagher, J.P. J. Neurosci. (2004) [Pubmed]
  8. Lack of association between the corticotrophin-releasing hormone receptor 2 gene and panic disorder. Tharmalingam, S., King, N., De Luca, V., Rothe, C., Koszycki, D., Bradwejn, J., Macciardi, F., Kennedy, J.L. Psychiatr. Genet. (2006) [Pubmed]
  9. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Lovenberg, T.W., Liaw, C.W., Grigoriadis, D.E., Clevenger, W., Chalmers, D.T., De Souza, E.B., Oltersdorf, T. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  10. Large-scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C. Kato, N., Ji, G., Wang, Y., Baba, M., Hoshida, Y., Otsuka, M., Taniguchi, H., Moriyama, M., Dharel, N., Goto, T., Shao, R.X., Matsuura, T., Ishii, K., Shiina, S., Kawabe, T., Muramatsu, M., Omata, M. Hepatology (2005) [Pubmed]
  11. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. Cao, J., Papadopoulou, N., Kempuraj, D., Boucher, W.S., Sugimoto, K., Cetrulo, C.L., Theoharides, T.C. J. Immunol. (2005) [Pubmed]
  12. 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]
  13. Corticotropin-releasing hormone receptor subtypes and emotion. Steckler, T., Holsboer, F. Biol. Psychiatry (1999) [Pubmed]
  14. Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Liaw, C.W., Lovenberg, T.W., Barry, G., Oltersdorf, T., Grigoriadis, D.E., de Souza, E.B. Endocrinology (1996) [Pubmed]
  15. Human CRF2 alpha and beta splice variants: pharmacological characterization using radioligand binding and a luciferase gene expression assay. Ardati, A., Goetschy, V., Gottowick, J., Henriot, S., Valdenaire, O., Deuschle, U., Kilpatrick, G.J. Neuropharmacology (1999) [Pubmed]
  16. The role of CRF2 receptors in corticotropin-releasing factor- and urocortin-induced anorexia. Smagin, G.N., Howell, L.A., Ryan, D.H., De Souza, E.B., Harris, R.B. Neuroreport (1998) [Pubmed]
  17. 125I-Tyro-sauvagine: a novel high affinity radioligand for the pharmacological and biochemical study of human corticotropin-releasing factor 2 alpha receptors. Grigoriadis, D.E., Liu, X.J., Vaughn, J., Palmer, S.F., True, C.D., Vale, W.W., Ling, N., De Souza, E.B. Mol. Pharmacol. (1996) [Pubmed]
  18. Identification and characterization of multiple corticotropin-releasing factor type 2 receptor isoforms in the rat esophagus. Wu, S.V., Yuan, P.Q., Wang, L., Peng, Y.L., Chen, C.Y., Taché, Y. Endocrinology (2007) [Pubmed]
  19. 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]
  20. The effect of lateral septum corticotropin-releasing factor receptor 2 activation on anxiety is modulated by stress. Henry, B., Vale, W., Markou, A. J. Neurosci. (2006) [Pubmed]
  21. Determinants of corticotropin releasing factor. Receptor selectivity of corticotropin releasing factor related peptides. Mazur, A.W., Wang, F., Tscheiner, M., Tcheiner, M., Donnelly, E., Isfort, R.J. J. Med. Chem. (2004) [Pubmed]
  22. Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. Sánchez, M.M., Young, L.J., Plotsky, P.M., Insel, T.R. J. Comp. Neurol. (1999) [Pubmed]
  23. Corticotropin-releasing hormone receptor (CRHR)1 and CRHR2 are both trafficking and signaling receptors for urocortin. Tu, H., Kastin, A.J., Pan, W. Mol. Endocrinol. (2007) [Pubmed]
  24. Vasodilator actions of urocortin and related peptides in the human perfused placenta in vitro. Leitch, I.M., Boura, A.L., Botti, C., Read, M.A., Walters, W.A., Smith, R. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  25. 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]
  26. Corticotrophin-releasing factor type 2 receptor-mediated suppression of gonadotrophin-releasing hormone mRNA expression in GT1-7 cells. Kinsey-Jones, J.S., Li, X.F., Bowe, J.E., Lightman, S.L., O'byrne, K.T. Stress (Amsterdam, Netherlands) (2006) [Pubmed]
  27. Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides. Kauser, S., Slominski, A., Wei, E.T., Tobin, D.J. FASEB J. (2006) [Pubmed]
  28. Characterisation using microphysiometry of CRF receptor pharmacology. Smart, D., Coppell, A., Rossant, C., Hall, M., McKnight, A.T. Eur. J. Pharmacol. (1999) [Pubmed]
  29. Corticotropin-releasing hormone, its binding protein and receptors in human cervical tissue at preterm and term labor in comparison to non-pregnant state. Klimaviciute, A., Calciolari, J., Bertucci, E., Abelin-Tornblöm, S., Stjernholm-Vladic, Y., Byström, B., Petraglia, F., Ekman-Ordeberg, G. Reprod. Biol. Endocrinol. (2006) [Pubmed]
  30. 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]
  31. Urocortin 1, urocortin 3/stresscopin, and corticotropin-releasing factor receptors in human adrenal and its disorders. Fukuda, T., Takahashi, K., Suzuki, T., Saruta, M., Watanabe, M., Nakata, T., Sasano, H. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  32. Localization of the human CRF2 receptor to 7p21-p15 by radiation hybrid mapping and FISH analysis. Meyer, A.H., Ullmer, C., Schmuck, K., Morel, C., Wishart, W., Lübbert, H., Engels, P. Genomics (1997) [Pubmed]
  33. Urocortin 3/stresscopin in human colon: possible modulators of gastrointestinal function during stressful conditions. Saruta, M., Takahashi, K., Suzuki, T., Fukuda, T., Torii, A., Sasano, H. Peptides (2005) [Pubmed]
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