Abstract
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 human (h) MRAP2 splice variants, MRAP2b (465 bp open reading frame) and MRAP2c (381 bp open reading frame). Human MRAP2s are different in C-termini. We investigated the effects of five isoforms of MRAPs, hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c, on MC3R and MC4R pharmacology. At the hMC3R, hMRAP1a and hMRAP2c increased and hMRAP1b decreased the cell surface expression. hMRAP1a increased affinity to ACTH. Four MRAPs (hMRAP1a, hMRAP1b, hMRAP2a, and hMRAP2c) decreased the maximal responses in response to α-MSH and ACTH. For hMC4R, hMRAP1a, hMRAP2a, and hMRAP2c increased the cell surface expression of hMC4R. 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 trafficking, binding, and signaling. These findings led to a better understanding of the regulation of neural MCRs by MRAP1s and MRAP2s.
Highlights
Melanocortin receptors (MCRs), MC1R to MC5R, are members of rhodopsin-likeFamily A G-protein-coupled receptors (GPCRs) activated by melanocortin peptides including α, β, and γ-melanocyte-stimulating hormone (α, β, and γ-MSH) and adrenocorticotropic hormone (ACTH) [1,2]
No significant effect was observed for hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c on α-MSH affinities at the human MC4R (hMC4R) (Figure 6A and Table 3)
MRAP1a, MRAP2b, and MRAP2c had no effects on affinities of hMC4R to ACTH (Figure 6B and Table 3)
Summary
Melanocortin receptors (MCRs), MC1R to MC5R, are members of rhodopsin-likeFamily A G-protein-coupled receptors (GPCRs) activated by melanocortin peptides including α-, β-, and γ-melanocyte-stimulating hormone (α-, β-, and γ-MSH) and adrenocorticotropic hormone (ACTH) [1,2]. MC3R and MC4R (neural MCRs) are primarily expressed in the central nervous system [3,4,5,6] and play pivotal roles in regulating energy homeostasis [7,8]. Mice lacking Mc4r display morbid obesity with decreased energy expenditure and increased food intake [9,10]. Mc3r knockout mice have moderate obesity phenotype with normal food intake and metabolism, increased fat mass, and decreased lean mass [11,12,13]. These results indicate distinct non-redundant mechanisms between MC3R and MC4R in regulating energy homeostasis. MC3R is expressed in the periphery and may have other potential physiological functions in regulating cardiovascular function [19,20], immune response [21,22,23,24,25], natriuresis [26], and timing of sexual maturation [27]
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