The adrenocorticotropic hormone (ACTH) receptor, known as the melanocortin-2 receptor (MC2R), plays an important role in regulating adrenocortical function. The over-production of ACTH, such as in Cushing’s disease and in ectopic ACTH syndrome, can result in obesity, excessive morbidity and mortality.At present there is no effective medical treatment that would directly block the action of ACTH.The ACTH receptor (MC2R) is, therefore, a potential therapeutic target for blocking this ACTH effect.In this study, we examined the molecular basis of MC2R responsible for ligand selectivity.


Methods: The MC2R chimeric receptors or mutated receptors were constructed using MC2R wild type as a template.The receptor function was then examined.Student t test was used for statistical analysis, with p < 0.05 considered to be statistically significant.


1) ACTH1-17 is a full agonist at MC2R and MC3R wild-types (WT) but DPhe7-ACTH1-17 is agonist only for MC3RWT.Substitution of the upper region of the MC2R transmembrane domain 3 (TM3) with the corresponding region of the MC3R switches DPhe7-ACTH1-17 from no agonist activity to agonist.2) Four amino acid residues L109, F110, V111 and L112 of the TM3 of the MC2R were replaced with the corresponding residue of the MC3R (L109M, F110I, V111C and L112I).Our results indicate that when amino acid residue leucine 112 was changed to isoleucine (L112I).It switches DNal7-ACTH1-16 and MSH from no activity to full agonist.


MC2R TM3 is important for ligand selectivity and amino acid residue L112 in the TM3 is crucial for the ACTH or MSH selectivity.Our results provide the molecular basis of MC2R for the development of selective MC2R ligand for the treatment of adrenal disorders.