Melanocortin receptor accessory proteins in adrenal gland physiology and beyond

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 w20% 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. Hypothalamic-pituitary-adrenal axisThe adrenal glands are responsible for releasing different classes of hormones. The inner part of the glands, the medulla, secretes catecholamines under the control of the sympathetic nervous system. The outer part, the cortex, has three functionally distinct layers -the outer zona glomerulosa that secretes aldosterone, the middle zona fasciculata that produces glucocorticoids and the inner zona reticularis that is responsible for the production of adrenal androgens. Production and release of glucocorticoids by the zona fasciculata are tightly regulated by the hypothalamus and pituitary to control

Identification of Leydig cell-specific mRNA transcripts in the adult rat testis

“…Among other things, CD36 acts to facilitate fatty acid and lipoprotein uptake (He et al 2011) and so may contribute to the cellular pool of cholesterol esters. MRAP is essential for trafficking and functional expression of the ACTH receptor MC2R in the adrenal gland (Novoselova et al 2013). MC2R is functionally expressed in foetal Leydig cells in the mouse testis (O'Shaughnessy et al 2003) but not in adult Leydig cells, and there is no evidence of Mc2r expression in adult rat Leydig cells from this study.…”

Genomewide association studies of suicide attempts in US soldiers

“…A role for CEP162 , involved in required to promote assembly of the transition zone in primary cilia [Wang et al 2013], cannot be discounted, though it is not an obvious candidate. The product of MRAP2 , M2CR accessory protein, supports M2CR cell surface expression necessary for the production of a functional ACTH-responsive melanocortin receptor [Chan et al 2009; Novoselova et al 2013]. MRAP2 is expressed in brain and adrenal tissue, where it is involved with neural control of energy homeostasis, possibly through Mrap2 interaction with the melanocortin-4-receptor (Mc4r) affecting receptor signaling [Dores et al 2016; Jackson et al.…”

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

“…For instance, the melanocortin receptor accessory proteins (MRAPs) have recently been identified as single transmembrane-spanning proteins that modulate the expression, trafficking, and signaling of members of the melanocortin receptor (MCR) family with many similarities to RAMPs and their interacting GPCRs (Novoselova et al, 2013). The first MRAP was identified through a genetic screen in patients with familial glucocorticoid deficiency, and was found to be most highly expressed in the adrenal gland where it facilitates the cell-surface expression of MCR2 and makes the receptor responsive to adrenocorticotropic hormone (Metherell et al, 2005).…”

“…Similar to the RAMPs, the MRAPs show quite a wide expression pattern, which suggests that they likely serve other functions that go beyond trafficking and expression. Possibilities include the determination of MCR phenotype and signal coupling preferences (Novoselova et al, 2013). Given that approximately 20% of cases of familial glucocorticoid deficiency are caused by mutations in MRAP (Metherell et al, 2005), this highlights the potential for targeting the MCR-MRAP interaction for therapeutic purposes.…”