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Ca2+/Calmodulin Reverses Phosphatidylinositol 3,4,5-Trisphosphate-dependent Inhibition of Regulators of G Protein-signaling GTPase-activating Protein Activity

2000; Elsevier BV; Volume: 275; Issue: 25 Linguagem: Inglês

10.1074/jbc.m001128200

1083-351X

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

Cellular transport and secretion

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 (PIP 3 ) 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 PIP 3 but do not affect inhibition of GAP activity by palmitoylation. Conversely, the GAP activity of a palmitoylation-resistant mutant RGS4 is inhibited by PIP 3 . Calmodulin binds all RGS proteins we tested in a Ca 2+ -dependent manner but does not directly affect GAP activity. Indeed, Ca 2+ /calmodulin binds a complex of RGS4 and a transition state analog of Gα i1 -GDP-AlF 4 − . Ca 2+ /calmodulin reverses PIP 3 -mediated but not palmitoylation-mediated inhibition of GAP activity. Ca 2+ /calmodulin competition with PIP 3 may provide an intracellular mechanism for feedback regulation of Ca 2+ signaling evoked by G protein-coupled agonists.