Changes in ionic currents and β-adrenergic receptor signaling in hypertrophied myocytes overexpressing Gαq

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+/Ca2+ exchange currents were reduced in G alpha(q) myocytes. Consistent with functional measurements, Na+/Ca2+ 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 Ca2+ currents (I-Ca) in both groups, with a similar EC50, but the maximal response in G alpha(q) myocytes was similar to 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 similar to 55% of that in NTG myocytes. These results indicate that the changes in ionic currents and multiple defects in the beta-adrenergic receptor/Ca2+ channel signaling pathway contribute to altered ventricular function in this model of cardiac hypertrophy.