| dc.description.abstract | The melanocortin receptor (MCR) family consists of five G-protein coupled receptors
(MC1R-MC5R) involved in a wide range of physiological and disease processes.
MC2R is a critical component of the hypothalamic-pituitary-adrenal axis whilst MC3R
and MC4R have an essential role in energy homeostasis. Mutations in MC4R are the
most common cause of monogenic obesity. Investigating the way these receptors signal
and traffic to the surface is vital in understanding disease processes related to MCR
dysfunction.
The identification of MRAP in 2005 as the first and only MC2R accessory protein
provided insight into the regulation of the MCR system. Studies showed that MRAP
was responsible for adrenal MC2R trafficking and function. Mutations in MRAP cause
familial glucocorticoid deficiency, an autosomal recessive disorder resulting in isolated
cortisol deficiency.
MRAP2 is a novel conserved homologue of MRAP. In this study the role of MRAP2 as
an accessory protein to one or more MCR was analysed. MRAP2 mRNA is expressed in
the brain and adrenal gland. In heterologous cells, MRAP2 is a glycosylated protein
localised to the cell membrane and ER. On co-immunoprecipitation, MRAP2 can
homodimerise and heterodimerise with MRAP. Western blotting of tissues using an
MRAP2 antibody reveals an immunoreactive band of high molecular weight (~47.5
kDa) consistent with an MRAP2 dimer resistant to SDS and heat, a phenomenon similar
to endogenous MRAP. MRAP2 can interact with all five MCRs. This interaction results
in MC2R surface expression and signalling. In contrast, MRAP2 can reduce MC1R, MC3R, MC4R and MC5R responsiveness to NDP-MSH in the presence or absence of
MRAP. Furthermore, MRAP2 mRNA localisation in the hypothalamus and
paraventricular nucleus points to a potential accessory role in the central regulation of
MC4R and/or MC3R. In summary, this is the first report to identify MRAP2 as a unique
bidirectional regulator of the melanocortin receptor family. | en_US |
