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 (2). Each receptor subtype has characteristic size, tissue distribution and biological significance. The melanocortin system and its receptors regulate skin pigmentation, glucocorticoid production, and energy balance. The melanocortin receptors are as follows:

MC1-R is a 315 amino acid transmembrane protein. In humans it maps to 16q24 (3). It is the principal melanocortin receptor in the skin where it regulates pigmentation (4). It exhibits high affinity for most MSH isoforms and for ACTH. MC1-R exhibits the highest affinity towards alpha–MSH (Ki = 0.033 nmol/l). It is also present in the adrenals, leukocytes, lung, lymph node, ovary, testis, pituitary, placenta, spleen and uterus. The agouti protein is an endogenous antagonist of the MC1R in the skin (5). Overexpression of the agouti protein results in fair skin, reddish hair and disturbances of the energy balance.

MC2-R is the primary ACTH receptor. The ACTH / MC2 receptor is a 297 amino acid transmembrane G-protein coupled receptor (6). In humans it maps to 18p11.2 (3). Activation of the MC2 receptor initiates a cascade of events affecting multiple steps in corticoid steroidogenesis. Mutations in MC2-R may result in familial glucocorticoid deficiency, a group of autosomal recessive disorders characterized by resistance to ACTH. It should be noted that although the ACTH / MC2 receptor is expressed predominantly in the adrenal cortex, it is also present in skin melanocytes while its ligand ACTH binds to the MC1 receptor thus affecting skin pigmentation (4, 7, 8). Thus, chronically elevated ACTH in the circulation (chronic adrenal insufficiency, ectopic ACTH production or in Nelson’s syndrome following adrenalectomy) can induce skin and gum hyperpigmentation. MC2-R is also expressed in adipocytes and mediates stress-induced lipolysis via central ACTH release (9).

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. In humans it is a 360 amino acid protein whereas in mice and rats 323 amino acid (10). In humans it maps to 20q13.2 (3). It should be noted that the MC3-R and MC4-R in the Central Nervous System regulate food intake and energy homeostasis. MC3 and MC4-R knockouts are obese. However, the MC4 receptor KO mice are hyperphagic while the MC3 receptor KO animals are not hyperphagic but still obese (11). The agouti (ag) and the agouti related protein (argp) are endogenous natural antagonists of the MC1, MC3 and MC4 receptors (12). Finally, the MC3 receptor may be involve in the mechanism turning off the inflammatory response (13, 14).

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 (15). In humans, it maps to 18q22 (3). MC4-R is the principal melanocortin receptor for food intake regulation (16). Inactivating mutations of MC4 cause obesity both in mice and humans (17, 18).

The melanocortinergic system: As it was mentioned above, the melanocortinergic system in the central nervous system consists of the endogenous agonists alpha-, beta-, and gamma-MSH (post-translational products of POMC), the naturally occurring antagonists the agouti-related protein (AGRP) produced by the arcuate nucleus neurons in hypothalamus, and the agouti protein found in the skin. The AGRP 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. Mahogany protein is widely expressed and it is a close relative of Attractin, an immunoregulatory protein made by human T lymphocytes. Activation of the central melanocortin receptors (MC3 and MC4) by alpha MSH inhibits feeding and alters the rate of energy consumption leading to weight loss, whereas its blockade results in obesity (19, 20). Development of MC3R and MC4R knockout mice revealed differential actions of each receptor. MC4R -/- mice were hyperphagic with partially increased metabolic efficiency while MC3R-/- animals developed obesity due to increased metabolic efficiency, thus underlying their significance in metabolism and obesity (11, 21).

The MC4 receptor is also involved in the regulation of autonomic nervous system tone and of arterial pressure at the level of the central nervous system (22). The MC4 receptor appears to be also involved in several higher learning processes. Outside the central nervous system the MC4 receptor is expressed in osteoblasts where it may be involved in bone remodeling facilitating the communication between osteoblasts and osteoclasts (17).

MC5-R is a 325 amino acid transmembrane protein. It is expressed in the adrenals, skin, stomach, lung and spleen (6). Its levels in the central nervous system are very low. In 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. It is expressed in peripheral lymphocytes and in splenocytes indicating that this may be the receptor utilized by ACTH in those cells (23).