Changes in ionic currents and b-adrenergic receptor signaling in hypertrophied myocytes overexpressing Gaq

Mitarai, Sayaka, Thomas D. Reed, and Atsuko Yatani. Changes in ionic currents and b-adrenergic receptor signaling in hypertrophied myocytes overexpressing Gaq. Am J Physiol Heart Circ Physiol 279: H139–H148, 2000.—Transgenic overexpression of Gaq causes cardiac hypertrophy and depressed contractile responses to b-adrenergic receptor agonists. The electrophysiological basis of the altered myocardial function was examined in left ventricular myocytes isolated from transgenic (Gaq) mice. Action potential duration was significantly prolonged in Gaq compared with nontransgenic (NTG) myocytes. The densities of inward rectifier K currents, transient outward K currents (Ito), and Na /Ca exchange currents were reduced in Gaq myocytes. Consistent with functional measurements, Na/Ca exchanger gene expression was reduced in Gaq hearts. Kinetics or sensitivity of Ito to 4-aminopyridine was unchanged, but 4-aminopyridine prolonged the action potential more in Gaq myocytes. Isoproterenol increased L-type Ca currents (ICa) in both groups, with a similar EC50, but the maximal response in Gaq myocytes was ;24% of that in NTG myocytes. In NTG myocytes, the maximal increase of ICa with isoproterenol or forskolin was similar. In Gaq myocytes, forskolin was more effective and enhanced ICa up to ;55% of that in NTG myocytes. These results indicate that the changes in ionic currents and multiple defects in the b-adrenergic receptor/ Ca channel signaling pathway contribute to altered ventricular function in this model of cardiac hypertrophy.