Characterization of GRK2 RH domain-dependent regulation of GPCR coupling to heterotrimeric G proteins.
Heterotrimeric guanine nucleotide (G)-coupled receptors (GPCRs) form the largest family of integral membrane proteins. GPCR activation by an agonist promotes the exchange of GDP for GTP on the Galpha subunit of the heterotrimeric G protein. The dissociated Galpha and Gbetagamma subunits subsequently modulate the activity of a diverse assortment of effector systems. GPCR signaling via heterotrimeric G proteins is attenuated rapidly by the engagement of protein kinases. The canonical model for GPCR desensitization involves G protein-coupled receptor kinase (GRK)-dependent receptor phosphorylation to promote the binding of arrestin proteins that function to sterically block receptor:G-protein interactions. GRK2 and GRK3 have been shown to interact with Galphaq via the regulator of G-protein signaling (RGS) homology (RH) domain localized within their amino-terminal domains. It now appears that the G-protein uncoupling of many GPCRs linked to Galphaq, in particularly metabotropic glutamate receptors, may be mediated by the GRK2 RH domain via a phosphorylation-independent mechanism. This article reviews much of the background and methodology required for the characterization of the GRK2 phosphorylation-independent attenuation of GPCR signaling.
Biology Department, Siena College, Loudonville, New York 12211, USA.
Rachel
R
Sterne-Marr
Gurpreet K
GK
Dhami
John J G
JJ
Tesmer
Stephen S G
SS
Ferguson
D000818:Animals; D001681:Biological Assay / Q000379:methods; D001923:Brain Chemistry; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D043562:Receptors, G-Protein-Coupled; D018094:Receptors, Metabotropic Glutamate; D011993:Recombinant Fusion Proteins; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins