Changes in ionic currents and beta-adrenergic receptor signaling in hypertrophied myocytes overexpressing G alpha(q).
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.
Mitarai
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Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Reed
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TD
Yatani
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D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000503:physiopathology*; D002478:Cells, Cultured; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012016:Reference Values; D015398:Signal Transduction; D019831:Sodium-Calcium Exchanger / Q000235:genetics
D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D015761:4-Aminopyridine; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D007545:Isoproterenol