title: Phospholipase Cε hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy.
abstract: Phospholipase Cε (PLCε) is a multifunctional enzyme implicated in cardiovascular, pancreatic, and inflammatory functions. Here we show that conditional deletion of PLCε in mouse cardiac myocytes protects from stress-induced pathological hypertrophy. PLCε small interfering RNA (siRNA) in ventricular myocytes decreases endothelin-1 (ET-1)-dependent elevation of nuclear calcium and activation of nuclear protein kinase D (PKD). PLCε scaffolded to muscle-specific A kinase-anchoring protein (mAKAP), along with PKCε and PKD, localizes these components at or near the nuclear envelope, and this complex is required for nuclear PKD activation. Phosphatidylinositol 4-phosphate (PI4P) is identified as a perinuclear substrate in the Golgi apparatus for mAKAP-scaffolded PLCε. We conclude that perinuclear PLCε, scaffolded to mAKAP in cardiac myocytes, responds to hypertrophic stimuli to generate diacylglycerol (DAG) from PI4P in the Golgi apparatus, in close proximity to the nuclear envelope, to regulate activation of nuclear PKD and hypertrophic signaling pathways.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Lianghui
authors.initials: L
authors.lastname: Zhang
authors.forename: Sundeep
authors.initials: S
authors.lastname: Malik
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Pang
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Keigan M
authors.initials: KM
authors.lastname: Park
authors.forename: David I
authors.initials: DI
authors.lastname: Yule
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006321:Heart; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009685:Nuclear Envelope / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D054801:Phosphoinositide Phospholipase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
chemical_list: D018129:Phosphatidylinositol Phosphates; C037178:phosphatidylinositol 4-phosphate; D054801:Phosphoinositide Phospholipase C; C506061:Plch1 protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
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