Selective regulation of Gα(q/11) by an RGS domain in the G protein- coupled receptor kinase, GRK2

Christopher V. Carman, Jean Luc Parent, Peter W. Day, Alexey N. Pronin, Pamela M. Sternweis, Philip B. Wedegaertner, Alfred G. Gilman, Jeffrey L. Benovic, Tohru Kozasa

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288 Scopus citations


G protein-coupled receptor kinases (GRKs) are well characterized regulators of G protein-coupled receptors, whereas regulators of G protein signaling (RGS) proteins directly control the activity of G protein α subunits. Interestingly, a recent report (Siderovski, D. P., Hessel, A., Chung, S., Mak, T. W., and Tyers, M. (1996) Curr. Biol. 6, 211-212) identified a region within the N terminus of GRKs that contained homology to RGS domains. Given that RGS domains demonstrate AlF4/--dependent binding to G protein α subunits, we tested the ability of G proteins from a crude bovine brain extract to bind to GRK affinity columns in the absence or presence of AlF4/-. This revealed the specific ability of bovine brain Gα(q/11) to bind to both GRK2 and GRK3 in an AlF4/--dependent manner. In contrast, Gα(s), Gα(i), and Gα(12/13) did not bind to GRK2 or GRK3 despite their presence in the extract. Additional studies revealed that bovine brain G2a(q11) could also bind to an N-terminal construct of GRK2, while no binding of Gα(q/11), Gα(s), Gα(i), or Gα(12/13) to comparable constructs of GRK5 or GRK6 was observed. Experiments using purified Gα(q) revealed significant binding of both Gα(q) GDP/AlF4/- and Gα(q)(GTPγS), but not Gα(q)(GDP), to GRK2. Activation-dependent binding was also observed in both COS-1 and HEK293 cells as GRK2 significantly co-immunoprecipitated constitutively active Gα(q)(R183C) but not wild type Gα(q). In vitro analysis revealed that GRK2 possesses weak GAP activity toward Gα(q) that is dependent on the presence of a G protein-coupled receptor. However, GRK2 effectively inhibited Gα(q)-mediated activation of phospholipase C-β both in vitro and in cells, possibly through sequestration of activated Gα(q). These data suggest that a subfamily of the GRKs may be bifunctional regulators of G protein-coupled receptor signaling operating directly on both receptors and G proteins.

Original languageEnglish (US)
Pages (from-to)34483-34492
Number of pages10
JournalJournal of Biological Chemistry
Issue number48
StatePublished - Nov 26 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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