MRAP2 (Melanocortin Receptor Accessory Protein Two) and its role in melanocortin receptor trafficking and expression
MetadataShow full item record
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.
- Theses