Endocrine Abstracts

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, whilst MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function.

The melanocortin receptor accessory proteins, 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 approximately 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 fetal gland, is unclear.

The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R mediated adrenal steriodogenesis. In vitro, MRAPs have been shown to reduce surface expression and signaling of all the other melanocortin receptors (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 central nervous system role for the MRAPs.