E. Reiter et al., Kinase-inactive G-protein-coupled receptor kinases ave able to attenuate follicle-stimulating hormone-induced signaling, BIOC BIOP R, 282(1), 2001, pp. 71-78
Citations number
38
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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 fina
lly binding of beta -arrestin to phosphorylated receptors and functional un
coupling of the associated Ga protein. It has recently been reported that G
RKs can inhibit Gag-mediated signaling in the absence of phosphorylation of
some GPCRs. Whether or not comparable phosphorylation-independent effects
are also possible with G alphas-coupled receptors remains unclear. In the p
resent study, using the tightly G alphas-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 up
stream of adenylyl cyclase activation and are likely independent of GRK int
eraction with G protein alpha or beta/gamma subunits. Moreover, we demonstr
ated that, when overexpressed in Cos 7 cells, mutated GRK2 associates with
the FSH activated FSH-R. We hypothesize that phosphorylation-independent da
mpening of the FSH-R-associated signaling could be attributable to physical
association between GRKs and the receptor, subsequently inhibiting G; prot
ein activation. (C) 2001 Academic Press.