Involvement of melanocortin receptor accessory proteins (MRAPs) in the function of melanocortin receptors J.M. Cerdá-Reverter ⇑ , M.J. Agulleiro, R. Cortés, E. Sánchez, R. Guillot, E. Leal, B. Fernández-Durán, S. Puchol, M. Eley Department of Fish Physiology and Biotechnology, Instituto de Acuicultura de Torre de la Sal, Consejo Superior de Investigaciones Científicas (IATS-CSIC), 12595 Torre de la Sal, Ribera de Cabanes, Castellón, Spain article info Article history: Available online xxxx Keywords: Melanocortin MRAP ACTH MSH Accessory protein HPA axis abstract The melanocortin system integrates different agonists, competitive or inverse agonists, and receptors. Recent investigations have also discovered a specific system of melanocortin receptor accessory proteins (MRAPs) that are involved in the regulation of the functional expression of these receptors. MRAP1 muta- tions are responsible for type 2 familial glucocorticoid deficiency (FGD2), a rare autosomal disorder char- acterized by high plasma adrenocorticotropin hormone (ACTH) levels but severe cortisol deficiency. ACTH binds melanocortin 2 receptor (MC2R), a G protein-coupled receptor, in the adrenal gland to pro- mote corticosteroid synthesis. In the absence of MRAP1, MC2R cannot translocate from the endoplasmic reticulum to the plasma membrane and ACTH-induced signaling is extinguished. A second MRAP protein, called MRAP2, also modulates MC2R activity. MRAPs also interact with the other melanocortin receptors, adjusting their pharmacological properties. In this paper, we briefly review the MRAP system and its interaction with melanocortin receptors. Ó 2013 Elsevier Inc. All rights reserved. 1. Melanocortin system Melanocortins are posttranscriptional products of a complex precursor named proopiomelanocortin (POMC). They are mainly comprised of an adrenocorticotropic hormone (ACTH) and melano- cyte-stimulating hormones (a-, b- c- and d-MSH). Tetrapod POMC precursor comprises three main domains: the N-terminal pro-c- MSH, the central ACTH and the C-terminal b-lipotropin. Each do- main contains one MSH peptide delineated by a core sequence HFRW: c-MSH in pro-c-MSH, b-MSH as N-terminal sequence of ACTH and b-MSH in b-lipotropin domain (Nakanishi et al., 1979). Tetrapod POMC is mainly produced in the vertebrate pituitary and its posttranslational processing occurs in a tissue-specific manner. The proteolytic cleavage of POMC by prohormone conver- tase 1 (PC1) generates ACTH and b-lipotropin (b-LPH) in the corti- cotrophs of the anterior pituitary, whereas cleavage by PC1 and PC2 produces a-MSH and b-endorphin in the melanotrophs of the pars intermedia. POMC is also centrally produced and mainly processed to a-MSH and b-endorphin (Castro and Morrison, 1997). In rodents, two discrete groups of neurons in the hypothal- amus (arcuate nucleus) and the medulla (nucleus of the tractus sol- itarius) also produce POMC (Bangol et al., 1999). POMC mRNA expression within the mediobasal hypothalamus has been con- served throughout vertebrate evolution, as POMC transcripts have been detected in hypothalamic neuronal systems of amphibians (Tuinhof et al., 1998), birds (Gerets et al., 2000) and fish (Cerdá-Re- verter and Peter, 2003). However, no POMC expression within the vagal lobe, the teleostean nucleus of the tractus solitarius, has been reported in any teleost species. Melanocortin exerts its physiological role by binding to a family of specific G protein-coupled receptors that positively couple to adenylyl cyclase. Tetrapod species have five melanocortin recep- tors (MC1R–MC5R). The extracellular and cytoplasmic tails of all of the melanocortin receptors are unusually short. In fact, the MC2 receptor is the smallest of the hundreds of identified GPCRs. In mammalian systems, MC2R is specific for ACTH. By contrast, the MSHs bind to the other four MCRs, with MC1R and MC3R exhibiting the highest affinity for a-MSH and c-MSH, respectively (Schiöth et al., 2007). Atypically, melanocortin signaling is not exclusively regulated by the binding of endogenous agonists, as naturally occurring antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP) compete with melanocortin peptides by binding to MCRs. ASP is a potent melanocortin antag- onist at melanocortin MC1R and MC4R receptors and relatively weak at MC3R. In contrast, AGRP is mainly produced within the hypothalamic arcuate nucleus and the adrenal gland, where it strongly inhibits melanocortin signaling at MC3R and MC4R, but it is not active at MC1R (Cone, 2006). Several studies have demon- strated that mammalian ASP and AGRP work as inverse agonists at 0016-6480/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygcen.2013.01.017 ⇑ Corresponding author. Fax: +34 964319509. E-mail address: cerdarev@iats.csic.es (J.M. Cerdá-Reverter). General and Comparative Endocrinology xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen Please cite this article in press as: Cerdá-Reverter, J.M., et al. Involvement of melanocortin receptor accessory proteins (MRAPs) in the function of mela- nocortin receptors. Gen. Comp. Endocrinol. (2013), http://dx.doi.org/10.1016/j.ygcen.2013.01.017