title: G protein βγ subunits regulate cardiomyocyte hypertrophy through a perinuclear Golgi phosphatidylinositol 4-phosphate hydrolysis pathway.
abstract: 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), PLCε, at the nuclear envelope. How stimuli are transmitted from cell surface GPCRs to activation of perinuclear PLCε is not clear. Here we tested the role of G protein βγ subunits. Gβγ inhibition blocked ET-1-stimulated Golgi PI4P depletion in neonatal and adult ventricular myocytes. Blocking Gβγ at the Golgi inhibited ET-1-dependent PI4P depletion and nuclear PKD activation. Translocation of Gβγ to the Golgi stimulated perinuclear Golgi PI4P depletion and nuclear PKD activation. Finally, blocking Gβγ at the Golgi or PM blocked ET-1-dependent cardiomyocyte hypertrophy. These data indicate that Gβγ 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 Gβγ inhibition in preventing heart failure maybe due in part to its blocking both these pathways.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
authors.forename: S
authors.initials: S
authors.lastname: Malik
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
authors.forename: R G
authors.initials: RG
authors.lastname: deRubio
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
authors.forename: M
authors.initials: M
authors.lastname: Trembley
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: R
authors.initials: R
authors.lastname: Irannejad
authors.affiliation: Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: P B
authors.initials: PB
authors.lastname: Wedegaertner
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642.
authors.forename: A V
authors.initials: AV
authors.lastname: Smrcka
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D002478:Cells, Cultured; D044387:GTP-Binding Protein beta Subunits / Q000502:physiology*; D044388:GTP-Binding Protein gamma Subunits / Q000502:physiology*; D006056:Golgi Apparatus / Q000378:metabolism*; D006868:Hydrolysis; D032383:Myocytes, Cardiac / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems
chemical_list: C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D018129:Phosphatidylinositol Phosphates; C037178:phosphatidylinositol 4-phosphate