Emerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology.

Berruien, N. and Smith, C.L. 2020. Emerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology. Gene. 757 144949. https://doi.org/10.1016/j.gene.2020.144949

TitleEmerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology.
TypeJournal article
AuthorsBerruien, N. and Smith, C.L.
AbstractMelanocortin-2 receptor accessory protein (MRAP) has an unusual dual topology and influences the expression, localisation, signalling and internalisation of the melanocortin receptor 2 (MC ); the adrenocorticotropic hormone (ACTH) receptor. Mutations in MRAP are associated with familial glucocorticoid deficiency type-2 and evidence is emerging of the importance of MRAP in adrenal development and ACTH signalling. Human MRAP has two functional splice variants: MRAP-α and MRAP-β, unlike MRAP-β, MRAP-α has little expression in brain but is highly expressed in ovary. MRAP2, identified through whole human genome sequence analysis, has approximately 40% sequence homology to MRAP. MRAP2 facilitates MC2 localisation to the cell surface but not ACTH signalling. MRAP and MRAP2 have been found to regulate the surface expression and signalling of all melanocortin receptors (MC ). Additionally, MRAP2 moderates the signalling of the G-protein coupled receptors (GCPRs): orexin, prokineticin and GHSR1a; the ghrelin receptor. Whilst MRAP appears to be mainly involved in glucocorticoid synthesis, an important role is emerging for MRAP2 in regulating appetite and energy homeostasis. Transgenic models indicate the importance of MRAP in adrenal gland formation. Like MC3R and MC4R knockout mice, MRAP2 knockout mice have an obese phenotype. In vitro studies indicate that MRAP2 enhances the MC3 and MC4 response to the agonist αMSH, which, like ACTH, is produced through precursor polypeptide proopiomelanocortin (POMC) cleavage. Analysis of cohorts of individuals with obesity have revealed several MRAP2 genetic variants with loss of function mutations which are causative of monogenic hyperphagic obesity with hyperglycaemia and hypertension. MRAP2 may also be associated with female infertility. This review summarises current knowledge of MRAP and MRAP2, their influence on GPCR signalling, and focusses on pathophysiology, particularly familial glucocorticoid deficiency type-2 and obesity. [Abstract copyright: Copyright © 2020 Elsevier B.V. All rights reserved.]
KeywordsACTH
Adrenal gland
Alpha-MSH
Dual topology
Familial glucocorticoid deficiency
Female infertility
Ghrelin
Glucocorticoid
MC1R
MC2
MC2R
MC3R
MC4R
MC5R
MRAP
MRAP2
Melanocortin 2 receptor accessory protein
Melanocortin receptor
Obesity
melanocortin
Article number144949
JournalGene
Journal citation757
ISSN1879-0038
Year2020
PublisherElsevier
Accepted author manuscript
License
CC BY-NC-ND 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1016/j.gene.2020.144949
PubMed ID32679290
Publication dates
Published online15 Jul 2020
Published in print05 Oct 2020

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