The role of MRAPs in the control of melanocortin receptor dependent energy homeostasis and adrenal function

The ‘melanocortin receptors‘ are an important group of proteins which are found on the surface of cells at many places in the body. They are responsible for a large number of different processes such as food metabolism, feeding behaviour and stress responses. Diseases which can present in childhood, such as severe obesity and the inability to fight infections, arise when these receptors fail to work properly. In the laboratory we have now identified two other proteins called MRAPs (Melanocortin Receptor Accessory Proteins) that affect the way in which the melanocortin receptors work. By studying the MRAP proteins in cells, and what happens when the MRAP proteins are absent, we will better understand how the MRAP/Melanocortin receptors work together, and how defects in them could lead to disease. In the long-term this understanding may help in the development of new drugs for the treatment of conditions such as obesity.

The Melanocortin Receptor (MCR) family consists of five G protein-coupled receptors (MC1R to MC5R) which have a diverse role in human physiological and disease processes. MC1R is important in pigmentation, MC2R in steriodogenesis and MC5R has an exocrine function especially in sebaceous gland secretion. MC3R and MC4R are both highly expressed in the brain and play key roles in energy homeostasis. Mutations in MC4R are the most common cause of monogenic obesity. More recently, fat mass, weight, risk of obesity and insulin resistance were associated with common variants near the MC4R locus. Both MC4R knockout mice and humans with MC4R mutations display early onset obesity associated with hyperphagia. MC3R knockout mice, however, develop a milder phenotype with later onset obesity.
MRAP (Melanocortin-2-receptor accessory protein) is a small transmembrane MC2R accessory protein that enables the functional expression of MC2R. Mutations in MRAP result in the autosomal recessive disorder, Familial Glucocorticoid Deficiency type 2.
More recently, we identified and characterised a novel MRAP homologue highly expressed in the brain, which we have named MRAP2. We showed that the MRAPs were novel bidirectional regulators of the MCR family. MRAPs can interact with all five members of the MCR family, and in doing so regulate cell surface receptor expression and signalling. Both MRAP and MRAP2 are expressed in the hypothalamus, in regions where MC3R and MC4R are known to be expressed. This suggests that the MRAPs may play an important role in vivo in regulating appetite and weight. MRAP2 is also expressed in the adrenal gland and may play a role in adrenal function and/or development.
The ultimate aim of this Fellowship is to further characterise the role of MRAPs on MCR function and to establish the in vivo role of MRAPs in energy homeostasis and adrenal function. I hypothesise that: (1) MRAPs affect MCR binding and ligand specificity (2) Changes in the expression of MRAP and MRAP2 will affect MC3R and MC4R expression and signalling, hence disrupt and alter feeding behaviour, energy homeostasis and fat mass in murine models (3) MRAP2, in addition to the already established role of MRAP, plays an important role in adrenal function and/or development.
The potential medical and scientific opportunities are great as therapeutic manipulation of the melanocortin receptors is at the forefront of pharmacological research.