Deciphering complexities in ghrelin receptor signalling to enhance understanding of appetite regulation

Understanding how the brain regulates appetite is essential for identifying therapeutic targets for obesity and undernutrition, which are increasingly prevalent in ageing populations. Ghrelin, the ‘hunger hormone’ is produced by the stomach and tells the brain when to eat and store fat. Ghrelin does this by binding to the growth hormone secretagogue receptor-1a (GHSR1a) on brain cell surfaces. GHSR1a is a G-protein-coupled receptor (GPCR), so-called because it associates with G-proteins that initiate message relays (signalling), to decide cell responses. GHSR1a seems an ideal drug target for manipulating hunger, but GHSR1a inhibitors are ineffective. This could be because signalling by GHSR1a is more complex than previously thought. In this fellowship I will investigate how GHSR1a may achieve this complexity. I will assess: how GHSR1a clusters with other GPCRs in brain tissue; how interacting proteins influence GHSR1a signalling and movement around cells (trafficking); and whether activating other GPCRs influences ghrelin-mediated physiological functions.