Endocrine Abstracts

An intact pituitary-adrenal axis is essential for life, yet is entirely dependent on a system with no inbuilt redundancy. Central to its activity a single peptide hormone, ACTH, acts on a single G protein-coupled receptor (GPCR) at the adrenal cortex. This ACTH receptor, otherwise known as the Melanocortin 2 receptor (MC2R) is the smallest of all GPCRs, consequently being highly hydrophobic and lacking a signal sequence – hence its resemblance to a “blob”. Multiple and varied attempts to demonstrate functional expression of this receptor were unsuccessful, and it became apparent that an adrenal-specific co-factor was required. Genetic exploration of the basis of Familial Glucocorticoid Deficiency type 2 revealed the existence of a small protein that we called the Melanocortin Receptor Accessory Protein (MRAP). MRAP exists in a unique antiparallel homodimer structure interacting with the MC2R at the endoplasmic reticulum, and trafficking with it to the plasma membrane where it is required for ACTH-dependent signal generation. In contrast to MC2R, MRAP protein turns over quite rapidly and it seems likely that this results in significant amounts of uncombined (MRAP-free) MC2R at the cell surface – spare receptor. In evolution, MRAP arose through duplication of an older MRAP-like gene, MRAP2, and has developed a highly specialized role in conjunction with the MC2R. MRAP2 appears to have a far more diverse role, interacting with multiple GPCRs in the hypothalamus and elsewhere and exhibiting a complex role in the regulation of feeding and metabolism. Further understanding of the biology of these proteins should provide potential new targets for therapeutic manipulation.