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Type: Journal article
Title: Regulation of the epithelial Na⁺ channel by the RH domain of G protein-coupled receptor kinase, GRK2, and Gαq/11
Other Titles: Regulation of the epithelial Na(+) channel by the RH domain of G protein-coupled receptor kinase, GRK2, and G alpha q/11
Author: Lee, I.
Song, S.
Campbell, C.
Kumar, S.
Cook, D.
Dinudom, A.
Citation: Journal of Biological Chemistry, 2011; 286(22):19259-19269
Publisher: Amer Soc Biochemistry Molecular Biology Inc
Issue Date: 2011
ISSN: 0021-9258
Statement of
Il-Ha Lee, Sung-Hee Song, Craig R. Campbell, Sharad Kumar, David I. Cook, and Anuwat Dinudom
Abstract: The 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 α-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 (K220RGRK2), but not a GRK2 mutant that lacks the C-terminal RH domain (ΔRH-GRK2) or a GRK2 mutant that cannot interact with Gαq/11/14 (D110AGRK2), increase activity of ENaC. GRK2 up-regulates the basal activity of the channel as a consequence of its RH domain binding the α-subunits of Gq/11. We further found that expression of constitutively active Gαq/11 mutants significantly inhibits activity of ENaC. Conversely, co-expression of siRNA against Gαq/11 increases ENaC activity. The effect of Gαq 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 α-subunits regulate the activity ENaC.
Keywords: Epithelial Cells
Rats, Inbred F344
GTP-Binding Protein alpha Subunits, Gq-G11
Ubiquitin-Protein Ligases
Amino Acid Substitution
Gene Expression Regulation
Protein Structure, Tertiary
Mutation, Missense
G-Protein-Coupled Receptor Kinase 2
Endosomal Sorting Complexes Required for Transport
HEK293 Cells
Epithelial Sodium Channels
Nedd4 Ubiquitin Protein Ligases
Rights: © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M111.239772
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