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pubmed-article:21464134pubmed:abstractTextThe G protein-coupled receptor kinase (GRK2) belongs to a family of protein kinases that phosphorylates agonist-activated G protein-coupled receptors, leading to G protein-receptor uncoupling and termination of G protein signaling. GRK2 also contains a regulator of G protein signaling homology (RH) domain, which selectively interacts with ?-subunits of the Gq/11 family that are released during G protein-coupled receptor activation. We have previously reported that kinase activity of GRK2 up-regulates activity of the epithelial sodium channel (ENaC) in a Na(+) absorptive epithelium by blocking Nedd4-2-dependent inhibition of ENaC. In the present study, we report that GRK2 also regulates ENaC by a mechanism that does not depend on its kinase activity. We show that a wild-type GRK2 (wtGRK2) and a kinase-dead GRK2 mutant ((K220R)GRK2), but not a GRK2 mutant that lacks the C-terminal RH domain (?RH-GRK2) or a GRK2 mutant that cannot interact with G?q/11/14 ((D110A)GRK2), increase activity of ENaC. GRK2 up-regulates the basal activity of the channel as a consequence of its RH domain binding the ?-subunits of Gq/11. We further found that expression of constitutively active G?q/11 mutants significantly inhibits activity of ENaC. Conversely, co-expression of siRNA against G?q/11 increases ENaC activity. The effect of G?q on ENaC activity is not due to change in ENaC membrane expression and is independent of Nedd4-2. These findings reveal a novel mechanism by which GRK2 and Gq/11 ?-subunits regulate the activity ENaC.lld:pubmed
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pubmed-article:21464134pubmed:articleTitleRegulation of the epithelial Na+ channel by the RH domain of G protein-coupled receptor kinase, GRK2, and Galphaq/11.lld:pubmed
pubmed-article:21464134pubmed:affiliationDiscipline of Physiology, The Bosch Institute, Faculty of Medicine, The University of Sydney, Sydney, NSW 2006, Australia.lld:pubmed
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pubmed-article:21464134pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
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