title: MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family.
abstract: The melanocortin receptor (MCR) family consists of 5 G protein-coupled receptors (MC1R-MC5R) with diverse physiologic roles. MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, whereas MC3R and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the single most common cause of monogenic obesity. Investigating the way in which these receptors signal and traffic to the cell membrane is vital in understanding disease processes related to MCR dysfunction. MRAP is an MC2R accessory protein, responsible for adrenal MC2R trafficking and function. Here we identify MRAP2 as a unique homologue of MRAP, expressed in brain and the adrenal gland. We report that MRAP and MRAP2 can interact with all 5 MCRs. This interaction results in MC2R surface expression and signaling. In contrast, MRAP and MRAP2 can reduce MC1R, MC3R, MC4R, and MC5R responsiveness to [Nle4,D-Phe7]alpha-melanocyte-stimulating hormone (NDP-MSH). Collectively, our data identify MRAP and MRAP2 as unique bidirectional regulators of the MCR family.
authors.affiliation: Queen Mary University of London, Centre for Endocrinology, St. Bartholomew's and Royal London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom.
authors.forename: Li F
authors.initials: LF
authors.lastname: Chan
authors.forename: Tom R
authors.initials: TR
authors.lastname: Webb
authors.forename: Teng-Teng
authors.initials: TT
authors.lastname: Chung
authors.forename: Eirini
authors.initials: E
authors.lastname: Meimaridou
authors.forename: Sadani N
authors.initials: SN
authors.lastname: Cooray
authors.forename: Leonardo
authors.initials: L
authors.lastname: Guasti
authors.forename: J Paul
authors.initials: JP
authors.lastname: Chapple
authors.forename: Michaela
authors.initials: M
authors.lastname: Egertová
authors.forename: Maurice R
authors.initials: MR
authors.lastname: Elphick
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark