Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2007) 14 OC9.1

ECE2007 Oral Communications Signal transduction (7 abstracts)

Investigation of the role of MRAP in the functional expression of the melanocortin 2 receptor

Sadani Cooray , Lou Metherell , Mike Cheetham & Adrian Clark


William Harvey Research Institite, London, United Kingdom; Institute of Ophthalmology, London, United Kingdom.


Mutations in the ACTH receptor (Melanocortin 2 receptor/MC2R) are associated with Familial Glucocorticoid Deficiency/FGD. FGD is an autosomal recessive disorder that results from ACTH insensitivity at the adrenal cortex. However, only about 25% of FGD are caused by mutations in the MC2R suggesting the genetically heterogeneous nature of the disease. The transfection-mediated functional expression of the MC2R can only be achieved in cell lines of adrenal origin implying that the receptor may require an adrenal specific accessory factor/factors for functional expression. The causative gene for FGD type 2 (normal MC2R) was identified in our lab. It encoded a novel single transmembrane domain protein of unknown function that we subsequently named MRAP (melanocortin receptor accessory protein). We demonstrated that MRAP assists the MC2R to the cell surface as determined by confocal microscopy on CHO and SKN-SH cells. MRAP was also shown to play a role in the production of a functional MC2R in these cell lines as was indicated by the enhanced cAMP response to ACTH when co-transfected with MC2R and MRAP (Metherell L.A., et al., Nature Genetics 2005 37 166–170). The knockdown of MRAP expression by transient transfection of MRAP siRNA (small interfering RNA) duplexes in Y1 mouse adrenocortical cells resulted in a reduction in MC2R signalling as determined by the significant decrease in cAMP when stimulated with ACTH. The expression and function of MRAP was restored in the clonal cell lines expressing mouse MRAP shRNAs by the transfection of the human MRAP sequence. Co-immunoprecipitation studies showed an interaction between MRAP and MC2R but not the other four melanocortin receptors. The production of cAMP through MC1R, MC3R, MC4R and MC5R was not enhanced in the presence of MRAP. In summary MRAP was found to be essential for the functional expression of the MC2R.

Article tools

My recent searches

No recent searches.