Involvement of MRAPs in the function of fish melanocortin receptors (MCRs)

Abstract

Melanocortin signalling is mediated by binding to a family of G protein-coupled receptors that positively couple to adenylyl cyclase. Tetrapod spe cies have five melanocortin (MC1R-MC5R) receptors but the number of receptors varies in fis h. Zebrafish (zf), for example, have six melanocort in receptors, with two copies of the melanocortin MC5 receptor, while pufferfish have 4 receptors with no melanocortin MC3 receptor. MC2R specifically bin ds ACTH but requires the cooperation of the melanocortin receptor accessory protein (MRAP) to r each functional expression. The four other MCRs distinctively bind MSHs and show low affinity by AC TH. Two different MRAPs have been characterized in vertebrates, i.e MRAP1 and MRAP2. MRAP1 interacts with the MC2R to facilitate correct folding, subsequent glycosylation and cell surface expression but it is also essential for ACT H binding and ACTH-induced cAMP production. In the ab sence of MRAP, the MC2R is retained at the endoplasmic reticulum where it cannot be stimulated by ACTH. Both MRAP1 and MRAP2 have been also characterized in fish but, again, the number o f MRAPs diverges in teleost species. Zebrafish have three different MRAPs, with two copies of the MRAP2 , i.e MRAP2a and MRAP2b. Similar to tetrapod, zfMC2R is able to response to ACTH stimul ation only when coexpressed with MRAP1. Function of vertebrate MRAP2 is unknown but immunop recipitation studies demonstrate physical interaction with MCRs. In mammals, MRAP2 seems to b e an endogenous inhibitor that competes with MRAP1 for binding to MC2R anddecrease the pote ncy of adrenocorticotropic hormone (ACTH). However, it seems no to be the case in fish. The fu nction of MRAPs in the fish melanocortin system will be discussed.