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Endocrine Abstracts (2022) 86 PL4 | DOI: 10.1530/endoabs.86.PL4

Queen Mary University of London, London, United Kingdom


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.

Volume 86

Society for Endocrinology BES 2022

Harrogate, United Kingdom
14 Nov 2022 - 16 Nov 2022

Society for Endocrinology 

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