Melanocortin 2 receptor [1, 5] (MC2R [1, 3])

The Melanocortin 2 receptor (MC2R), also known as the adrenocorticotropic hormone (ACTH) receptor, is a G protein-coupled receptor primarily expressed in the adrenal cortex [1, 6]. It is unique among the melanocortin receptor family for its high specificity for ACTH and its absolute requirement for the accessory protein MRAP (Melanocortin 2 Receptor Accessory Protein) for proper trafficking and function [2, 12]. MC2R plays a critical role in the hypothalamic-pituitary-adrenal (HPA) axis by mediating the effects of ACTH on steroidogenesis, leading to the production of cortisol and other glucocorticoids [1, 9]. Mutations in the MC2R gene are a primary cause of familial glucocorticoid deficiency (FGD), while overactivity or overexpression is associated with Cushing's syndrome and congenital adrenal hyperplasia (CAH) [1, 5, 14]. Therapeutically, MC2R is targeted by ACTH analogs for diagnostic testing and treatment of inflammatory conditions, while small-molecule antagonists like atumelnant are being developed to treat conditions characterized by ACTH excess [5, 13, 14]. These antagonists aim to reduce adrenal androgen and cortisol overproduction without the need for high-dose glucocorticoid suppression [17, 18].

Other names

Adrenocorticotropic hormone receptor [1, 2]ACTH receptor [1, 6]ACTHR [2, 11]MC2-R [1, 5]hMC2R [1, 8]

Agonism of the receptor stimulates adenylyl cyclase and cAMP production, leading to steroidogenesis and cortisol release; antagonism blocks ACTH-mediated signaling to reduce cortisol levels [1, 3, 15].