melanocortins

The melanocortins are a family of neuropeptide hormones which are the ligands of the melanocortin receptors The melanocortin system consists of melanocortin receptors, ligands, and accessory proteins. The genes of the melanocortin system are found in chordates. Melanocortins were originally named so because their earliest known function was in melanogenesis. It is now known that the melanocortin system regulates diverse functions throughout the body, including inflammatory response, fibrosis, melanogenesis, steroidogenesis, energy homeostasis, sexual function, and exocrine gland function. There are four endogenous melanocortin agonists which are derived from post-transcriptional processing of the precursor molecule proopiomelanocortin (POMC) (Figure 1). They are Adrenocorticotropic hormone (ACTH), a-melanocyte stimulating hormone (MSH), b-MSH, and g-MSH. In addition to agonists which activate melanocortin receptors , there are two antagonists which inhibit receptor activity, Agouti and Agouti-related protein (Agrp). Lastly, the ligand β-defensin 3 acts as a neutral melanocortin receptor antagonist. Receptors The 5 melanocortin receptors are seven-transmembrane G-protein coupled receptors with differing ligand affinities, tissue and cell type expression, and downstream functions (Figure 2). MC1R is expressed on melanocytes, macrophages, epithelial cells, endothelial cells, fibroblasts, monocytes and numerous other immune cells, but is also present in brain, testis, and intestine. Its main functions are in melanogenesis and anti-inflammatory signaling. MC2R is expressed in the adrenal cortex and adipocytes and promotes steroidogenesis. MC3R and MC4R are primarily expressed in the brain and regulate energy homeostasis. MC3R is additionally involved in immunomodulation while MC4R has a role in sexual function. MC5R is highly expressed in skin and adrenal glands and has a role in exocrine function. MC2R is activated exclusively by ACTH, whereas the other 4 receptors can be activated by ACTH, a-MSH, b-MSH, and g-MSH, although the binding affinities differ. For all the melanocortin receptors, binding of an agonistic ligand activates the receptor, leading to dissociation of the G protein and activation of the enzyme adenyl cyclase. Adenyl cyclase then cleaves ATP to generate the second messenger cyclic AMP (cAMP), which in turn activates multiple downstream pathways.