Melanocortin-5 Receptor: Pharmacology and Its Regulation of Energy Metabolism

Abstract

As the most recent melanocortin receptor (MCR) identified, melanocortin-5 receptor (MC5R) has unique tissue expression patterns, pharmacological properties, and physiological functions. Different from the other four MCR subtypes, MC5R is widely distributed in both the central nervous system and peripheral tissues and is associated with multiple functions. MC5R in sebaceous and preputial glands regulates lipid production and sexual behavior, respectively. MC5R expressed in immune cells is involved in immunomodulation. Among the five MCRs, MC5R is the predominant subtype expressed in skeletal muscle and white adipose tissue, tissues critical for energy metabolism. Activated MC5R triggers lipid mobilization in adipocytes and glucose uptake in skeletal muscle. Therefore, MC5R is a potential target for treating patients with obesity and diabetes mellitus. Melanocortin-2 receptor accessory proteins can modulate the cell surface expression, dimerization, and pharmacology of MC5R. This minireview summarizes the molecular and pharmacological properties of MC5R and highlights the progress made on MC5R in energy metabolism. We poInt. out knowledge gaps that need to be explored in the future.

Keywords: energy metabolism; melanocortin-2 receptor accessory protein; melanocortin-5 receptor; pharmacology; signaling pathway.

Figure 1

Multiple functions of MC5R in various tissues.

Figure 2

Naturally occurring human MC5R mutations recorded in gnomAD database v2.1.1 (https://gnomad.broadinstitute.org/ (accessed on 13 April 2022)). The circles with gray background are missense and nonsense mutations/polymorphisms. Frameshift mutations are not shown here. The polymorphism (F209L) is labeled with a circle filled with red dashed lines. The most conserved residues in transmembrane domains (TMDs) are denoted in red font. DRY and DPxxY motifs are labeled in dashed line circles. MC5R secondary structures with extracellular loops (ECLs), transmembrane domains (TMDs), and intracellular (ICLs) loops are denoted in blue font.

Figure 3

Sequence alignment of multiple MC5Rs. The transmembrane (TM) regions are represented by blue shadow and are numbered 1–7. The 100% identical residues are indicated in red. MC5Rs: Homo sapiens (human, NP_005904.1), Mus musculus (mouse, NP_038624.3), Bubalus bubalis (water buffalo, XP_025129279.1), Cyanistes caeruleus (blue tit, XP_023777141.1), Chelonia mydas (green sea turtle, XP_007063924.1), Xenopus tropicalis (tropical clawed frog, NP_001096392.1), Danio rerio (zebrafish, NP_775386.1), and Larimichthys crocea (large yellow croaker, XP_010746135.1).

Figure 4

Comparative synteny analysis of MC5R. Chromosomal location and adjacent genes of MC5R are shown in different species. Genes with conserved synteny between at least two species are shown in the boxes with the same color (except the white box).

Figure 5

Human MC5R (A), MRAP1 (B), and MRAP2 (C) mRNA expression in various tissues, based on https://www.proteinatlas.org/ (accessed on 14 July 2022) [85]. nTPM indicates normalized protein-coding transcripts per million. Color coding is based on tissue groups with functional features in common.

Figure 6

Schematic diagram of MC5R signaling pathways in lipid and glucose metabolism.