Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases

Abstract

Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.

Keywords: genetic polymorphism; inflammatory disorders; melanocortin receptors (MCR); repository corticotropin injection (RCI).

Figure 1

The synthesis of various melanocortin peptides from post-translational processing of the POMC gene. ‘POMC’—pro-opiomelanocortin, ‘PC-1′—Proconvertase-1, ‘PC-2′—Proconvertase 2, ‘ACTH’—Adrenocorticotropic hormone, ‘MSH’—Melanocyte stimulating hormone, ‘CLIP’—Corticotropin-like intermediate lobe peptide.

Figure 2

Summary of key implications of melanocortin system in various pathologies. ‘MC1R’—melanocortin receptor 1, ‘MC3R’—melanocortin receptor 3, ‘MC4R-KO’—melanocortin receptor 4 knock out, ‘MC5R’—melanocortin receptor 5, ‘NDP-α-MSH’—Nle4-D-Phe7-α-Melanocyte stimulating hormone, ‘HCC’— hepatocellular carcinoma, ‘CCl4’—carbon tetrachloride, ‘ACTH’—adrenocorticotropic hormone, ‘MCN’—melanocortin, ‘IL-10’—interleukin 10, ‘FDA’—Food and Drug Administration U.S.A.