Cardiac-specific overexpression of Galphaq alters excitation-contraction coupling in isolated cardiac myocytes.
Transgenic mice with cardiac-specific overexpression of G alpha q 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, Ca(2+)transients, and l -type Ca(2+)channel currents (I(Ca)) in left ventricular (LV) myocytes isolated from non transgenic (NT) controls or G alpha q hearts. Although baseline contractile function (% shortening) and the amplitude of Ca(2+)transients in G alpha q myocytes were similar to NT myocytes, the rates of cellular shortening and relengthening and the duration of Ca(2+)transients were prolonged in G alpha q myocytes. Myocytes from G alpha q 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 G alpha q myocytes compared to NT myocytes. The kinetic difference in inactivation was abolished when Ba(2+)was used as the charge carrier or when the sarcoplasmic reticulum (SR) Ca(2+)was depleted by ryanodine, suggesting that Ca(2+)-dependent inactivation is reduced in G alpha q myocytes due to altered SR Ca(2+)release. Consistent with this hypothesis, the function of SR as assessed by the maximal Ca(2+)uptake rates and the apparent affinity of SR Ca(2+)-ATPase for Ca(2+)was reduced in ventricles of G alpha q heart. These results suggest that the reduced SR function contributes to the depressed contractility associated with this form of cardiac hypertrophy.
Yatani
A
A
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. Yatania@uc.edu
Frank
K
K
Sako
H
H
Kranias
E G
EG
Dorn
G W
GW
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D004594:Electrophysiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors
D015220:Calcium Channels; D019204:GTP-Binding Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium