Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes

J Mol Cell Cardiol. 2018 Aug;121:51-59. doi: 10.1016/j.yjmcc.2018.06.002. Epub 2018 Jun 7.

Abstract

In cardiac myocytes activation of an exchange factor activated by cAMP (Epac) leads to activation of phospholipase Cε (PLCε)-dependent hydrolysis of phosphatidylinositol 4-phosphate (PI4P) in the Golgi apparatus a process critical for development of cardiac hypertrophy. Here we show that β-adrenergic receptor (βAR) stimulation does not stimulate this pathway in the presence of the broad spectrum phosphodiesterase (PDE) inhibitor IBMX, but selective PDE3 inhibition revealed βAR-dependent PI4P depletion. On the other hand, selective inhibition of PDE2 or PDE9A blocked endothelin-1 (ET-1) and cAMP-dependent PI4P hydrolysis by PLCε. Direct activation of protein kinase A (PKA), protein kinase G (PKG), or the atrial natriuretic factor (ANF) receptor abolished PI4P hydrolysis in response to multiple upstream stimuli. These results reveal distinct pools of cyclic nucleotides that either inhibit PLCε at the Golgi through PKA/PKG, or activate PLCε at the Golgi through Epac. These data together reveal a new mechanism by which ANF and selective PDE inhibitors can protect against cardiac hypertrophy.

Keywords: A kinase anchoring protein; Cardiac hypertrophy; Cyclic AMP; Epac; Golgi apparatus; Phosphatidylinositol 4-phosphate; Phosphodiesterase; Phospholipase C.

Publication types

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

MeSH terms

  • 1-Methyl-3-isobutylxanthine / administration & dosage
  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism
  • Animals
  • Atrial Natriuretic Factor / genetics
  • Cardiomegaly / genetics*
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cardiomyopathy, Hypertrophic / genetics
  • Cardiomyopathy, Hypertrophic / pathology
  • Cell Compartmentation / genetics*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Golgi Apparatus / drug effects
  • Golgi Apparatus / genetics*
  • Humans
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Nucleotides / genetics*
  • Nucleotides / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoinositide Phospholipase C / genetics*
  • Phosphoinositide Phospholipase C / metabolism
  • Phosphoric Diester Hydrolases / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta / genetics
  • Signal Transduction / genetics

Substances

  • A Kinase Anchor Proteins
  • Nucleotides
  • Phosphatidylinositol Phosphates
  • Receptors, Adrenergic, beta
  • phosphatidylinositol 4-phosphate
  • Atrial Natriuretic Factor
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Phosphoric Diester Hydrolases
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon
  • 1-Methyl-3-isobutylxanthine