PSUN97 Regulation of melanocortin-3 and -4 receptors by isoforms of melanocortin-2 receptor accessory protein 1 and 2

The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R and MC4R signaling. In the present study, we identified two new MRAP2 splice variants, MRAP2b (465 bp open reading frame) and MRAP2c (381 bp open reading frame). Human (h) MRAP2s are different in C-termini. We investigated effects of hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c on MC3R and MC4R pharmacology. At the hMC3R, hMRAP1a increased affinity to ACTH, and hMRAP1b decreased maximal binding (Bmax). All MRAPs decreased the maximal responses in response to ACTH. For hMC4R, hMRAP1a and hMRAP1b significantly decreased Bmax, and MRAP2a increased Bmax. Human MRAP1b significantly increased affinity to ACTH while MRAP2a decreased affinity to ACTH. Human MRAP1a increased ACTH potency. MRAPs also affected hMC4R basal activities, with hMRAP1s increasing and hMRAP2s decreasing the basal activities. In summary, the newly identified splicing variants, hMRAP2b and hMRAP2c, could regulate MC3R and MC4R pharmacology. The two MRAP1s and three MRAP2s had differential effects on MC3R and MC4R binding and signaling. These findings led to a better understanding of the regulation of neural MCRs by MRAP1s and MRAP2s. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.