Changes in ionic currents and beta-adrenergic receptor signaling in hypertrophied myocytes overexpressing G alpha(q)

Am J Physiol Heart Circ Physiol. 2000 Jul;279(1):H139-48. doi: 10.1152/ajpheart.2000.279.1.H139.

Abstract

Transgenic overexpression of G alpha(q) causes cardiac hypertrophy and depressed contractile responses to beta-adrenergic receptor agonists. The electrophysiological basis of the altered myocardial function was examined in left ventricular myocytes isolated from transgenic (G alpha(q)) mice. Action potential duration was significantly prolonged in G alpha(q) compared with nontransgenic (NTG) myocytes. The densities of inward rectifier K(+) currents, transient outward K(+) currents (I(to)), and Na(+)/Ca(2+) exchange currents were reduced in G alpha(q) myocytes. Consistent with functional measurements, Na(+)/Ca(2+) exchanger gene expression was reduced in G alpha(q) hearts. Kinetics or sensitivity of I(to) to 4-aminopyridine was unchanged, but 4-aminopyridine prolonged the action potential more in G alpha(q) myocytes. Isoproterenol increased L-type Ca(2+) currents (I(Ca)) in both groups, with a similar EC(50), but the maximal response in G alpha(q) myocytes was approximately 24% of that in NTG myocytes. In NTG myocytes, the maximal increase of I(Ca) with isoproterenol or forskolin was similar. In G alpha(q) myocytes, forskolin was more effective and enhanced I(Ca) up to approximately 55% of that in NTG myocytes. These results indicate that the changes in ionic currents and multiple defects in the beta-adrenergic receptor/Ca(2+) channel signaling pathway contribute to altered ventricular function in this model of cardiac hypertrophy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / physiology
  • Cardiomegaly / physiopathology*
  • Cells, Cultured
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / physiology*
  • Gene Expression Regulation
  • Heart / drug effects
  • Heart / physiology*
  • Heart / physiopathology
  • Heart Ventricles
  • Isoproterenol / pharmacology
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Transgenic
  • Myocardium / cytology
  • Potassium Channels / drug effects
  • Potassium Channels / physiology
  • Receptors, Adrenergic, beta / physiology*
  • Reference Values
  • Signal Transduction
  • Sodium-Calcium Exchanger / genetics

Substances

  • Calcium Channels, L-Type
  • Potassium Channels
  • Receptors, Adrenergic, beta
  • Sodium-Calcium Exchanger
  • 4-Aminopyridine
  • GTP-Binding Proteins
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Isoproterenol