Melanocortin receptor type 3 as a potential target for anti-inflammatory therapy

Abstract

Alpha-melanocyte stimulating hormone (alpha-MSH) and other melanocortin peptides are potent anti-inflammatory agents exhibiting efficacy in many animal models of acute and chronic inflammation. They are derived from a larger precursor molecule known as the POMC prohormone and are produced both centrally and peripherally. They exert their effect by binding to melanocortin receptors, of which five have been cloned and partially characterised. Agonism at these receptors leads to adenylate cyclase activation and subsequent increases in cAMP formation. Two receptors to date have been proposed to mediate the actions of the melanocortin peptides in an inflammatory scenario, the MC1 and 3-R, and here we discuss our findings proposing the MC3-R as a novel therapeutic target. The potential anti-inflammatory role for MC3-R is in its infancy, however, recent studies have shown that melanocortin peptides are effective in mice bearing a non-functional MC1-R (recessive yellow e/e mice). This ability to inhibit cell migration appears to be via inhibition in cytokine and adhesion molecule expression and is due to their abilities to interfere with cell signalling pathways. Identification of endogenous mediators of anti-inflammation, their receptors and the pathologies they are effective in, is of benefit to the medical community, and will hopefully have reduced side effects. We believe that specific small molecule agonists directed at MC3-R could be potential novel therapeutics for inflammatory conditions.