G protein βγ subunits regulate cardiomyocyte hypertrophy through a perinuclear Golgi phosphatidylinositol 4-phosphate hydrolysis pathway

We recently identified a novel GPCR-dependent pathway for regulation of cardiac hypertrophy that depends on Golgi phosphatidylinositol 4-phosphate (PI4P) hydrolysis by a specific isoform of phospholipase C (PLC), PLC epsilon, at the nuclear envelope. How stimuli are transmitted from cell surface GPCRs to activation of perinuclear PLC epsilon is not clear. Here we tested the role of G protein beta gamma subunits. G beta gamma inhibition blocked ET-1-stimulated Golgi PI4P depletion in neonatal and adult ventricular myocytes. Blocking G beta gamma at the Golgi inhibited ET-1-dependent PI4P depletion and nuclear PKD activation. Translocation of G beta gamma to the Golgi stimulated perinuclear Golgi PI4P depletion and nuclear PKD activation. Finally, blocking G beta gamma at the Golgi or PM blocked ET-1-dependent cardiomyocyte hypertrophy. These data indicate that G beta gamma regulation of the perinuclear Golgi PI4P pathway and a separate pathway at the PM is required for ET-1-stimulated hypertrophy, and the efficacy of G beta gamma inhibition in preventing heart failure maybe due in part to its blocking both these pathways.