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  • Title: Kinase-inactive G-protein-coupled receptor kinases are able to attenuate follicle-stimulating hormone-induced signaling.
    Author: Reiter E, Marion S, Robert F, Troispoux C, Boulay F, Guillou F, Crepieux P.
    Journal: Biochem Biophys Res Commun; 2001 Mar 23; 282(1):71-8. PubMed ID: 11263973.
    Abstract:
    Homologous desensitization of G-protein-coupled receptors (GPCR) is thought to occur in several steps: binding of G-protein-coupled receptor kinases (GRKs) to receptors, receptor phosphorylation, kinase dissociation, and finally binding of beta-arrestin to phosphorylated receptors and functional uncoupling of the associated Galpha protein. It has recently been reported that GRKs can inhibit Galphaq-mediated signaling in the absence of phosphorylation of some GPCRs. Whether or not comparable phosphorylation-independent effects are also possible with Galphas-coupled receptors remains unclear. In the present study, using the tightly Galphas-coupled FSR receptor (FSH-R) as a model, we observed inhibition of the cAMP-dependent signaling pathway using kinase-inactive mutants of GRK2, 5, and 6. These negative effects occur upstream of adenylyl cyclase activation and are likely independent of GRK interaction with G protein alpha or beta/gamma subunits. Moreover, we demonstrated that, when overexpressed in Cos 7 cells, mutated GRK2 associates with the FSH activated FSH-R. We hypothesize that phosphorylation-independent dampening of the FSH-R-associated signaling could be attributable to physical association between GRKs and the receptor, subsequently inhibiting G protein activation.
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