Phospholipase C epsilon scaffolds to muscle-specific A kinase anchoring protein (mAKAPbeta) and integrates multiple hypertrophic stimuli in cardiac myocytes.

ABSTRACT: To define a role for phospholipase C? (PLC?) signaling in cardiac myocyte hypertrophic growth, PLC? protein was depleted from neonatal rat ventricular myocytes (NRVMs) using siRNA. NRVMs with PLC? depletion were stimulated with endothelin (ET-1), norepinephrine, insulin-like growth factor-1 (IGF-1), or isoproterenol and assessed for development of hypertrophy. PLC? depletion dramatically reduced hypertrophic growth and gene expression induced by all agonists tested. PLC? catalytic activity was required for hypertrophy development, yet PLC? depletion did not reduce global agonist-stimulated inositol phosphate production, suggesting a requirement for localized PLC activity. PLC? was found to be scaffolded to a muscle-specific A kinase anchoring protein (mAKAP?) in heart and NRVMs, and mAKAP? localizes to the nuclear envelope in NRVMs. PLC?-mAKAP interaction domains were defined and overexpressed to disrupt endogenous mAKAP?-PLC? complexes in NRVMs, resulting in significantly reduced ET-1-dependent NRVM hypertrophy. We propose that PLC? integrates multiple upstream signaling pathways to generate local signals at the nucleus that regulate hypertrophy.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC3123069 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature