Effects of melanocortins on adrenal gland physiology

The melanocortin-2-receptor (MC(2) receptor), also known as the ACTH receptor, is a critical component of the hypothalamic-pituitary-adrenal axis. The importance of MC(2) receptor in adrenal physiology is exemplified by the condition familial glucocorticoid deficiency, a potentially fatal disease characterised by isolated cortisol deficiency. MC(2)receptor mutations cause ~25% of cases. The discovery of a MC(2) receptor accessory protein MRAP, mutations of which account for ~15%-20% of familial glucocorticoid deficiency, has provided insight into MC(2) receptor trafficking and signalling. MRAP is essential for the functional expression of MC(2) receptor. MRAP2, a novel homolog of MRAP, can also facilitate MC(2) receptor cell surface expression and function. Like MRAP, MRAP2 is a small transmembrane domain glycoprotein capable of homodimerising. In addition, MRAP/MRAP2 can heterodimerise. The presence of MRAP2 adrenal expression suggests a possible role for MRAP2 in adrenal physiology, which has yet to be elucidated. Importantly, new data shows that the MRAPs can interact with all the other melanocortin receptors (MC(1,3,4,5) receptor). In contrast to MC(2) receptor, this interaction results in reduced melanocortin receptor surface expression and signalling. MRAP2 is predominantly expressed in brain. Hypothalamic expression has been demonstrated for both MRAP and MRAP2. The ability of MRAPs to modulate different members of the melanocortin receptor family in a bidirectional manner is intriguing. Furthermore, central nervous system expression of MRAPs points to a role beyond MC(2) receptor mediated adrenal steroidogenesis.