Cardiac specific overexpression of Gαq alters excitation-contraction coupling in isolated cardiac myocytes

Transgenic mice with cardiac-specific overexpression of Gαq exhibit a biochemical and physiological phenotype of load-independent cardiac hypertrophy with contractile dysfunction. To elucidate the cellular basis for altered contractility, we measured cellular contraction, Ca²⁺ transients, and L-type Ca²⁺ channel currents (I(Ca) in left ventricular (LV) myocytes isolated from non transgenic (NT) controls or Gαq hearts. Although baseline contractile function (% shortening) and the amplitude of Ca²⁺ transients in Gαq myocytes were similar to NT myocytes, the rates of cellular shortening and relengthening and the duration of Ca²⁺ transients were prolonged in Gαq myocytes. Myocytes from Gαq hearts had larger cell capacitance but no change in I(Ca) density, voltage-dependence of activation and inactivation. The responses of I(Ca) to dihydropyridine drugs and a membrane permeable cAMP analog, 8-(4-chlorophenylthio) cAMP, were not altered; however, the time course of I(Ca) inactivation was significantly slower in Gαq myocytes compared to NT myocytes. The kinetic difference in inactivation was abolished when Ba²⁺ was used as the charge carrier or when the sarcoplasmic reticulum (SR) Ca²⁺ was depleted by ryanodine, suggesting that Ca²⁺-dependent inactivation is reduced in Gαq myocytes due to altered SR Ca²⁺ release. Consistent with this hypothesis, the function of SR as assessed by the maximal Ca²⁺ uptake rates and the apparent affinity of SR Ca²⁺-ATPase for Ca²⁺ was reduced in ventricles of Gαq heart. These results suggest that the reduced SR function contributes to the depressed contractility associated with this form of cardiac hypertrophy.