The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology

Abstract

The melanocortin-4 receptor (MC4R) was cloned in 1993 by degenerate PCR; however, its function was unknown. Subsequent studies suggest that the MC4R might be involved in regulating energy homeostasis. This hypothesis was confirmed in 1997 by a series of seminal studies in mice. In 1998, human genetic studies demonstrated that mutations in the MC4R gene can cause monogenic obesity. We now know that mutations in the MC4R are the most common monogenic form of obesity, with more than 150 distinct mutations reported thus far. This review will summarize the studies on the MC4R, from its cloning and tissue distribution to its physiological roles in regulating energy homeostasis, cachexia, cardiovascular function, glucose and lipid homeostasis, reproduction and sexual function, drug abuse, pain perception, brain inflammation, and anxiety. I will then review the studies on the pharmacology of the receptor, including ligand binding and receptor activation, signaling pathways, as well as its regulation. Finally, the pathophysiology of the MC4R in obesity pathogenesis will be reviewed. Functional studies of the mutant MC4Rs and the therapeutic implications, including small molecules in correcting binding and signaling defect, and their potential as pharmacological chaperones in rescuing intracellularly retained mutants, will be highlighted.

Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

“…extensive localization studies on rat showed that the MC4R is widely expressed in adult rat, including cortex, thalamus, hypothalamus, brainstem, spinal cord and epidermal melanocytes [15][16][17][18] . Many studies have established that MC4R plays an important role in regulating energy homeostasis, food intake, cardiovascular function and sexual function 19 . Recently MC4R was found in DRG 3 and astrocytes 20,21 , which are involved in the development and maintenance of neuropathic pain.…”

Melanocortin-4 Receptor in Fish: A Review

“…Regulating f o od intake and energy homeostasis: The roles of mammalian MC4R in regulating energy h o meostasis were well studied [7]. MC4R knockout mice exhibit maturity-onset obesity, hyperphagia, increased linear growth, hyperinsulinemia, hyperglycemia, and delayed meal termination and reduced sensitivity to cholecystokinin [13].…”

“…Takahashi et al [34] Cyclostomata Petromyzoniformes Lam p etra fluviatilis Haitina et al [35] Citation: Wen Modulating reproductive founction: Several recent studies suggested that the MC4R is also involved in modulating reproductive function through affecting the secretion of reproductive hormones, and consequent sexual maturation in fi sh [7]. Moreover, the MC4R was found to be highly expressed in gonads of several fi sh, such as goldfi sh [42], Ya-fi sh [30], and snakeskin gourami [45].…”

“…The fi ve melanocortin receptors are called melanocortin receptors 1-5 (MC1R-MC5R) based on the sequence of their cloning. They are all members of Family A G protein coupled receptors (GPCRs) consisting of seven transmembrane domains (TMs) connected by alternating intracellular and extracellular loops, with the N-terminus extracellular, and the C-terminus intracellular [5][6][7].…”

“…It has been p r oved that MC4R is involved in regulating energy homeostasis in mammals [7]. Knockout of the MC4R resulted in increased food intake and decreased energy expenditure therefore obesity in mouse [13].…”