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

J Biol Chem. 2011 Jul 1;286(26):23012-21. doi: 10.1074/jbc.M111.231993. Epub 2011 May 5.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myocytes, Cardiac / metabolism*
  • Nuclear Envelope / metabolism*
  • Organ Specificity / genetics
  • Phosphoinositide Phospholipase C / genetics
  • Phosphoinositide Phospholipase C / metabolism*
  • Protein Structure, Tertiary
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / genetics

Substances

  • A Kinase Anchor Proteins
  • Muscle Proteins
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon