Phosphorylation-independent attenuation of GPCR signalling.
The uncoupling of G-protein-coupled receptors (GPCRs) from their cognate heterotrimeric G proteins provides an essential physiological 'feedback' mechanism that protects against both acute and chronic overstimulation of receptors. The primary mechanism by which GPCR activity is regulated is the feedback phosphorylation of activated GPCRs by kinases that are dependent on second messengers, GPCR kinases (GRKs) and arrestins. It has recently become apparent, however, that GRK2-mediated regulation of GPCR responsiveness also involves a phosphorylation-independent component that requires both heterotrimeric G-protein alpha-subunit interactions and GPCR binding. Moreover, in addition to GRK2, a growing number of GPCR-interacting proteins might contribute to the phosphorylation-independent G-protein uncoupling of GPCRs. Here, new information about the mechanisms underlying this phosphorylation-independent regulation of receptor and G-protein coupling is reviewed.
Ferguson
Stephen S G
SS
J. Allyn Centre for Cell Biology, Robarts Research Institute, 100 Perth Drive, PO Box 5015, London, Ontario N6A 5K8, Canada. ferguson@robarts.ca
D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
D043562:Receptors, G-Protein-Coupled; D017346:Protein Serine-Threonine Kinases; D019204:GTP-Binding Proteins