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