Melanocortin 2 receptor (MC2R) (MC2R)

The Melanocortin 2 receptor (MC2R), widely known as the adrenocorticotropic hormone (ACTH) receptor, is a specialized G protein-coupled receptor (GPCR) primarily located in the adrenal cortex [UniProt: P33032]. It is distinguished from other melanocortin receptors by its high specificity for ACTH and its mandatory requirement for the Melanocortin 2 Receptor Accessory Protein (MRAP) for proper trafficking to the cell membrane and signaling [PubMed: 15741203]. Upon ACTH binding, MC2R triggers a cAMP-dependent signaling pathway that drives the synthesis and secretion of glucocorticoids like cortisol, which are essential for metabolic regulation and the physiological stress response [StatPearls: NBK535400]. Dysfunction of this receptor due to genetic mutations is a primary cause of Familial Glucocorticoid Deficiency (FGD) type 1, where patients suffer from severe adrenal insufficiency despite elevated ACTH [PubMed: 22896537]. Pharmacological modulation of MC2R currently involves synthetic ACTH analogs for diagnostic stimulation tests and the treatment of certain inflammatory conditions or infantile spasms [NCBI: PMC5390333]. Current therapeutic research is actively exploring the development of direct MC2R antagonists as a strategy to manage hypercortisolemic states, such as Cushing’s disease or Congenital Adrenal Hyperplasia (CAH), by preventing excessive adrenal stimulation [PubMed: 32663836].

Other names

Adrenocorticotropic hormone receptorACTH receptorACTHRMC2-RAdrenocorticotropin receptor

Agonism of the MC2R to stimulate the production of glucocorticoids; investigational antagonism to reduce cortisol secretion