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PIP 3 inhibition of RGS protein and its reversal by Ca 2+ /calmodulin mediate voltage-dependent control of the G protein cycle in a cardiac K + channel

2002; National Academy of Sciences; Volume: 99; Issue: 7 Linguagem: Inglês

10.1073/pnas.072073399

1091-6490

Masaru Ishii, Atsushi Inanobe, Yoshihisa Kurachi,

Protein Kinase Regulation and GTPase Signaling

Regulators of G protein signaling (RGS) accelerate intrinsic GTP hydrolysis on α subunits of trimeric G proteins and play crucial roles in the physiological regulation of G protein-mediated cell signaling. The control mechanisms of the action of RGS proteins per se are poorly clarified, however. We recently showed a physiological mode of action of a RGS protein in cardiac myocytes. The voltage-dependent formation of Ca 2+ /calmodulin facilitated the GTPase activity of RGS by an unidentified mechanism, which underlay the “relaxation” behavior of G protein-gated K + (K G ) channels. Here we report the mechanism which is the reversal by Ca 2+ /calmodulin of phosphatidylinositol-3,4,5,-trisphosphate (PIP 3 )-mediated inhibition of RGS. Purified RGS4 protein alone inhibited GTP-induced K G channel activity in inside-out patches from atrial myocytes. The inhibitory effect of RGS4 was reduced by PIP 3 and restored by addition of Ca 2+ /calmodulin. The intracellular application of anti-PIP 3 antibody abolished the RGS-dependent relaxation behavior of K G current in atrial myocytes. This study, therefore, reveals a general physiological control mechanism of RGS proteins by lipid–protein interaction.