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Phospholipase C? hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy.


ABSTRACT: Phospholipase C? (PLC?) is a multifunctional enzyme implicated in cardiovascular, pancreatic, and inflammatory functions. Here we show that conditional deletion of PLC? in mouse cardiac myocytes protects from stress-induced pathological hypertrophy. PLC? 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). PLC? scaffolded to muscle-specific A kinase-anchoring protein (mAKAP), along with PKC? 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 PLC?. We conclude that perinuclear PLC?, 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.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC3615249 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Phospholipase Cε hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy.

Zhang Lianghui L   Malik Sundeep S   Pang Jinjiang J   Wang Huan H   Park Keigan M KM   Yule David I DI   Blaxall Burns C BC   Smrcka Alan V AV  

Cell 20130301 1


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), a  ...[more]

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