G Protein-Coupled Receptor (GPCR) Signalling
G-protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors. They share a common 7 transmembrane domain configuration and act to transduce extracellular stimuli to the interior of the cell. GPCRs are expressed in virtually every cell type and modulate an extremely wide range of physiological processes. They represent a rich source of targets for the pharmaceutical industry with approximately 30-50% of current pharmaceuticals targeting these proteins. Following repeated or continuous exposure to agonists GPCRs exhibit diminished responsiveness, a phenomenon termed receptor desensitisation. For many GPCRs rapid desensitisation is mediated by a family of serine/threonine kinases, the G protein-coupled receptor kinases (GRKs). GRKs phosphorylate agonist-occupied GPCRs and the phosphorylated receptor serves as a binding site for a member of the arrestin family. Arrestin binding uncouples the GPCR from G proteins and targets the phosphorylated receptor for internalisation via clathrin-coated pits. Given their role in regulating GPCR function it is not surprising that changes in the expression levels, or activities, of the GRKs are associated with a number of disease states. For example, elevated levels of GRK2 and 5 are responsible for alterations in myocardial function in chronic heart failure. In addition to their role in mediating GPCR desensitisation several lines of evidence suggest the GRKs have other cellular functions. It is our aim to elucidate at the molecular level the cellular functions of the GRKs, work which may aid in the design of therapeutically useful GRK inhibitors. We aim to (1) investigate the potential nuclear functions of GRKs, (2) investigate GRKs as G protein effectors, (3) identify novel binding partners and functions for GRKs and arrestins and (4) identify GRK family-specific inhibitors.