The Melanocortin System Family
The ACTH receptor is a seven transmembrane domain protein coupled to a guanine nucleotide binding protein (Gs), which activates adenyl cyclase. The human ACTH receptor gene has been cloned and it belongs to the melanocortin receptor family (MC-R) classified as melanocortin receptor 2 (MC2-R). The family of melanocortin receptors includes five members. Each receptor subtype has particular characteristics, tissue distribution and biologic significance. The Melanocortin system and the receptors regulate skin pigmentation, glucocorticoid production, and energy balance. The melanocortin receptors are as follows] hyperpigmentation. MC2R is also expressed in adipocytes and mediates stress-induced lipolysis via central ACTH release.

The fact that the ACTH receptor belongs to the melanocortin receptor family implies close association between several physiological processes including stress, homeostasis, regulation of food intake and regulation of energy balance, immunity and skin function. Indeed, ACTH can bind in melanocytes, adipocytes, mononuclear / macrophage cells, skin, and various areas of the central nervous system.
MC3-R is expressed in the brain. It should be pointed out that the MC3R and MC4R in the Central Nervous System regulate food intake and energy homeostasis. MC3 and MC4R knockouts are obese. However, the MC4 receptor KO mice are hyperphagic while the MC3 receptor KO animals are not hyperphagic but still obese. The agouti and the agouti related protein (argp) are endogenous natural antagonists of the MC1, MC3 and MC4 receptors. Finally, the MC3 receptor may be involve in the mechanism turning off the inflammatory response.
MC4-R is a 332 amino acid transmembrane protein. It is expressed in the central nervous system (mainly in the hypothalamus), the gastrointestinal tract and the placenta. In humans, it maps to 18q22. MC4-R is the principal melanocortin receptor for food intake regulation. Inactivating mutations of MC4 cause obesity both in mice and humans.

Melanocortinergic System]AGRP[/b] antagonizes alpha-MSH in the hypothalamus at the level of MC3 and MC4 receptors. The agouti protein and AGRP require the presence of a third protein, the mahogany to antagonize MSH (PubMed]The MC4R is involved in the regulation of autonomic nervous system tone and of arterial pressure at the level of the central nervous system. The MC4 receptor appears to be also in several higher learning processes in humans. Outside the central nervous system the MC4receptor is expressed in osteoblasts where melanocortins may be involved in bodybuilding facilitating the communication between osteoblasts and osteoclasts.

MC5-R is a amino acid transmembrane protein with newly found supporting features. It is expressed in the adrenals, skin, stomach, lung and spleen. Levels in the central nervous system are very low for the 5th melanocortin-receptor. The adrenal cortex it is expressed in all three layers but predominantly in the aldosterone-producing zona glomerulosa cells. In the skin it affects the exocrine function and is expressed peripherally in lymphocytes indicating there may be the receptor utilized by ACTH nearby or in the cells.