CRF2 receptor

Overview

Complementary DNAs for the CRF₂ receptor, a.k.a. CRHR2, have also been isolated from large number of vertebrate species [1,2,3,4,5,6,7,8,9,10,11]. Three functional splice variants [8,9,12] have been identified for the mammalian... [read more] CRF₂ receptor. The CRF(2a) receptor variant is only expressed in non-mammalian species [1,2,3,11], while the 430-438 amino-acid CRF_(2b) receptor and the CRF_(2a) receptor are both expressed in mammals [4,5,6,8,9,10,12]. Expression of the 397-amino acid CRF_(2c) receptor has only been detected in limbic regions of the human central nervous system [9]. Splicing of the CRF₂ receptor variants occurs at the extreme 5'-terminus of the receptor gene and reflects usage of different promoters in man. The hCRF2 gene, which is located on chromosome 7p14-15, is ñ50 kb in size and contains 15 exons [13]. The first four exons give rise to the different 5'-ends of the splice variants hCRF2(a), hCRF2(b) and hCRF_2(c), respectively; exons 5-15 form the common parts of the various hCRF₂ splice variants. Exons 1 and 2, which are separated by ñ10.5 kb intronic sequence encode the CRF_2(b)-specific part, followed by the CRF_2(c) and CRF_2(a) exons [13].

In rodents, CRF_(2a) receptor mRNA is expressed primarily in brain neurons while CRF_(2b) receptor mRNA is detected in non-neuronal brain structures and peripheral tissues [14]. The CRF_(2a) receptor is the dominant CRF₂ receptor splice variant expressed in the mammalian brain and is mainly found in areas that are critically involved in the mediation of stress responses [15,16]. In humans and tree shrews, CRF_(2a) receptor mRNA expression is broader than in rodent brain [10,17]. Because CRF_(2b) receptor mRNA can be detected in neuronal structures the distribution of these two splice variants may overlap in primates and primate-like animals. In the periphery, substantial expression of CRF₂ receptor can be found in the heart, skeletal muscle, vasculature, and gastrointestinal tract. The CRF_2(a) receptor is the major splice variant found in the peripheral tissues of humans [8,9], while the CRF_2(b) splice variant is the CRF₂ receptor peripherally expressed in rodents. The main expression sites for the rodent CRF_(2b) receptor have been reported for heart, lung, skeletal muscle, gastrointestinal tract, testis and ovaries [10,14].

Pharmacological characterization of the CRF₂ receptor splice variants revealed no major differences between CRF_(2a), CRF_(2b) and CRF_(2c) receptors [9,10,18,19]. However, the binding profiles of these three CRF₂ receptors strongly diverge from the binding profile of the CRF₁ receptor [6,18,20,21,22,23]. The non-mammalian CRF peptides urotensin I and sauvagine and the mammalian peptides urocortin 1, urocortin 2 and urocortin 3 generally bind with up to 100-fold higher affinities to the CRF₂ receptor than species homologues of CRF. In agreement with the binding data, a similar rank order of potency is typically observed when stimulation of intracellular cyclic AMP accumulation is measured [6,18,20,21,22]. Therefore, current evidence suggests that urocortin 2 and urocortin 3 represent the endogenous ligands for mammalian CRF₂ receptor variants. Urocortin 1 is an endogenous ligand with equal potencies in activating CRF₁ and CRF₂ receptors.

References

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4. Lovenberg TW, Liaw CW, Grigoriadis DE, et al. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc Natl Acad Sci USA 1995;92:836-40.
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7. Stenzel P, Kesterson R, Yeung W, et al. Identification of a novel murine receptor for corticotropin-releasing hormone expressed in the heart. Mol Endocrinol 1995;9:637-45.
8. Liaw CW, Lovenberg TW, Barry G, et al. Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology 1996;137:72-7.
9. Valdenaire O, Giller T, Breu V, et al. A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor. Biochim Biophys Acta 1997;1352:129-32.
10. Kostich WA, Chen A, Sperle K, et al. Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2gamma receptor. Mol Endocrinol 1998;12:1077-85.
11. Palchaudhuri MR, Hauger RL, Wille S, et al. Isolation and pharmacological characterization of two functional splice variants of corticotropin-releasing factor type 2 receptor from Tupaia belangeri. J Neuroendocrinol 1999;11:419-28.
12. Dautzenberg FM, Gutknecht E, Van der Linden I, et al. Cell type specific calcium signaling by corticotropin-releasing factor type 1 (CRF1) and 2a (CRF2(a)) receptors: Gq coupling in human embryonic kidney 293 but not SK-N-MC neuroblastoma cells. Biochem Pharmacol 2004;68:1833-1844.
13. de Groef B, Grommen SV, Mertens I, et al. Cloning and tissue distribution of the chicken type 2 corticotropin-releasing hormone receptor. Gen Comp Endocrinol 2004;138:89-95.
14. Dautzenberg FM, Huber G, Higelin J, et al. Evidence for the abundant expression of arginine 185 containing human CRF(2alpha) receptors and the role of position 185 for receptor-ligand selectivity. Neuropharmacology 2000;39:1368-76.
15. Bittencourt JC, Vaughan J, Arias C, et al. Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors. J Comp Neurol 1999;415:285-312.
16. Lovenberg TW, Chalmers DT, Liu C, et al. CRF2 alpha and CRF2 beta receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 1995;136:4139-4142.
17. Li C, Vaughan J, Sawchenko PE, et al. Urocortin III-immunoreactive projections in rat brain: partial overlap with sites of type 2 corticotrophin-releasing factor receptor expression. J Neurosci 2002;22:991-1001.
18. Donaldson CJ, Sutton SW, Perrin MH, et al. Cloning and characterization of human urocortin. Endocrinology 1996;137:2167-70.
19. Sánchez MM, Young LJ, Plotsky PM, et al. Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 1999;408:365-77.
20. Reyes TM, Lewis K, Perrin MH, et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci USA 2001;98:2843-8.
21. Hsu SY, Hsueh AJ. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 2001;7:605-11.
22. Dautzenberg FM, Py-Lang G, Higelin J, et al. Different binding modes of amphibian and human corticotropin-releasing factor type 1 and type 2 receptors: evidence for evolutionary differences. J Pharmacol Exp Ther 2001;296:113-20.
23. Perrin MH, Sutton SW, Cervini LA, et al. Comparison of an agonist, urocortin, and an antagonist, astressin, as radioligands for characterization of corticotropin-releasing factor receptors. J Pharmacol Exp Ther 1999;288:729-34.

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