Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2009) 19 P247

SFEBES2009 Poster Presentations Pituitary (56 abstracts)

The specificity of ACTH recognition by the MC2R

Teng-Teng Chung & Adrian Clark


Barts and the London School of Medicine, London, UK.


Background: The ACTH receptor (melanocortin 2 receptor – MC2R) is unique in that it is highly selective for ACTH and excludes all other MSH peptides. This contrasts with all other members of the melanocortin receptor family, which show broader specificity. The specificity of recognition of ACTH by the MC2R appears to depend on the presence of four basic residues, lysine, lysine, arginine, arginine at positions 15–18. Of α-, β- and γ-MSH are either identical to, or highly homologous to the first 13 residues of ACTH and therefore lack these basic residues. Examination of the MC2R sequence reveals four extra acidic residues in the extracellular domains when compared to the MC1,3,4 and 5 receptors.

Aim: To test the hypothesis that the acidic-basic residue interaction determines the high selectivity of the MC2R for ACTH.

Methods: Using site-directed mutagensis of the MC2R, the four acidic residues (E9, D20, E99 and D104) were replaced individually and in all combinations with alaine. These were transiently expressed in HEK293-MRAPα cells which stably express the MRAPα accessory protein for the MC2R. Signalling activity was measured using a co-transfected cAMP responsive-luciferase reporter system.

Results: All four single mutations demonstrated good cell surface expression by confocal microscopy. The 15 possible combinations of MC2R substitutions were transfected and stimulated with ACTH1–39 (10−7 M) and α-MSH (10−7 M). Results were expressed as α-MSH signal/ACTH signal and showed increased responsiveness when any two or three acidic residues were substituted and maximal activity when either all four residues or D20, E99 and D104 were replaced.

Conclusions: These findings are consistent with the hypothesis that interaction between the basic ‘core’ of ACTH and the identified acidic residues in MC2R are an essential event in ligand recognition by this receptor and may explain the inability of MSH peptides to activate MC2R.

Article tools

My recent searches

No recent searches.

My recently viewed abstracts