Co-ordinated covalent modification of G-protein coupled receptors

The G-protein coupled receptor (GPCR) gene family represents one of the largest families in the mammalian genome. The flexibility of signalling and widespread tissue distribution of these receptors has allowed GPCRs to be employed in the physiological regulation of nearly all biological functions. This, coupled with the fact that it is possible to chemically produce highly specific ligands to these receptors have made GPCRs attractive targets for pharmacological intervention in a wide variety of disease states. When targeting GPCRs in therapeutic drug design it is traditional, and eminently sensible, to focus on ligands that will provide agonism, antagonism or allosteric modulation. However, as more is understood of the mechanisms that regulate GPCRs, and in particular the dynamic covalent modifications that might endow tissue specific functions, then these regulatory processes may provide alternative targets for GPCR drug discovery. In this review we consider three of the covalent modifications which are considered to regulate the function of GPCRs namely; receptor phosphorylation, palmitoylation and ubiquitination. In particular, we will describe the mechanisms of modification, the functional consequences and the relationship between these three covalent modification events.