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.
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA. Yatania@uc.edu
A
A
Yatani
K
K
Frank
H
H
Sako
E G
EG
Kranias
G W
GW
Dorn
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