Ca2+/calmodulin reverses phosphatidylinositol 3,4,5-trisphosphate- dependent inhibition of regulators of G protein-signaling GTPase-activating protein activity

Serguei G. Popov, U. Murali Krishna, J R Falck, Thomas M Wilkie

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101 Scopus citations

Abstract

Regulators of G protein signaling (RGS proteins) are GTPase-activating proteins (GAPs) for G(i) and/or G(q) class G protein α subunits. RGS GAP activity is inhibited by phosphatidylinositol 3,4,5-trisphosphate (PIP3) but not by other lipid phosphoinositides or diacylglycerol. Both the negatively charged head group and long chain fatty acids (C16) are required for binding and inhibition of GAP activity. Amino acid substitutions in helix 5 within the RGS domain of RGS4 reduce binding affinity and inhibition by PIPs but do not affect inhibition of GAP activity by palmitoylation. Conversely, the GAP activity of a palmitoylation-resistant mutant RGS4 is inhibited by PIP3. Calmodulin binds all RGS proteins we tested in a Ca2+-dependent manner but does not directly affect GAP activity. Indeed, Ca2+/calmodulin binds a complex of RGS4 and a transition state analog of Gα(i1)-GDP-AlF4 -. Ca2+/calmodulin reverses PIP3-mediated but not palmitoylation-mediated inhibition of GAP activity. Ca2+/calmodulin competition with PIP3 may provide an intracellular mechanism for feedback regulation of Ca2+ signaling evoked by G protein-coupled agonists.

Original languageEnglish (US)
Pages (from-to)18962-18968
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number25
DOIs
Publication statusPublished - Jun 23 2000

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ASJC Scopus subject areas

  • Biochemistry

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