Melanocortin receptor accessory proteins in adrenal gland physiology and beyond T V Novoselova, D Jackson, D C Campbell, A J L Clark and L F Chan Centre for Endocrinology, Queen Mary University of London, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M6BQ, UK. Correspondence should be addressed to L F Chan Email l.chan@qmul.ac.uk 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. Key Words " MRAPs " Melanocortin receptor " HPA axis " Adrenal cortex Journal of Endocrinology (2013) 217, R1–R11 Hypothalamic–pituitary–adrenal axis The 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 pro- duction of adrenal androgens. Production and release of glucocorticoids by the zona fasciculata are tightly regulated by the hypothalamus and pituitary to control diurnal cortisol levels and the rapid increase of cortisol secretion during emotional or physical stress. Stress triggers a number of brain circuits such as brainstem catecholamine-producing pathways that cause excitation of the parvocellular neurons of the hypothalamic para- ventricular nucleus (PVN; reviewed in Herman & Cullinan (1997) and Arnsten (2009)). In response to stress, these neurons start secreting corticotropin-releasing hormone Journal of Endocrinology Review T V NOVOSELOVA and others Melanocortin receptor accessory proteins 217 :1 R1–R11 http://joe.endocrinology-journals.org Ñ 2013 Society for Endocrinology DOI: 10.1530/JOE-12-0501 Printed in Great Britain Published by Bioscientifica Ltd. Downloaded from Bioscientifica.com at 02/18/2023 10:02:13AM via free access