Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

Novoselova, Tatiana ORCID: https://orcid.org/0000-0002-2394-4667, Jackson, David, Campbell, David, Clark, Adrian and Chan, Li F. (2013) Melanocortin receptor accessory proteins in adrenal gland physiology and beyond. Journal of Endocrinology, 217 (1) . R1-R11. ISSN 0022-0795 [Article] (doi:10.1530/JOE-12-0501)

Abstract

The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R–MC5R) with diverse physiological roles. MC1R controls pigmentation, MC2R is a critical component of the hypothalamic–pituitary–adrenal axis, MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency, where inactivating MRAP mutations account for ∼20% of cases. MRAP is highly expressed in both the zona fasciculata and the undifferentiated zone. Expression in the undifferentiated zone suggests that MRAP could also be important in adrenal cell differentiation and/or maintenance. In contrast, the role of adrenal MRAP2, which is highly expressed in the foetal gland, is unclear. The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R-mediated adrenal steroidogenesis. In vitro, MRAPs have been shown to reduce surface expression and signalling of all the other MCRs (MC1,3,4,5R). MRAP2 is predominantly expressed in the hypothalamus, a site that also expresses a high level of MC3R and MC4R. This raises the intriguing possibility of a CNS role for the MRAPs.

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