Abnormal contraction caused by expression of G(i)-coupled receptor in transgenic model of dilated cardiomyopathy.
Although increased G(i) signaling has been associated with dilated cardiomyopathy in humans, its role is not clear. Our goal was to determine the effects of chronically increased G(i) signaling on myocardial function. We studied transgenic mice that expressed a G(i)-coupled receptor (Ro1) that was targeted to the heart and regulated by a tetracycline-controlled expression system. Ro1 expression for 8 wk resulted in abnormal contractions of right ventricular muscle strips in vitro. Ro1 expression reduced myocardial force by >60% (from 35 +/- 3 to 13 +/- 2 mN/mm(2), P < 0.001). Nevertheless, sensitivity to extracellular Ca(2+) was enhanced. The extracellular [Ca(2+)] resulting in half-maximal force was lower with Ro1 expression compared with control (0.41 +/- 0.05 vs. 0.88 +/- 0.05 mM, P < 0.001). Ro1 expression slowed both contraction and relaxation kinetics, increasing the twitch time to peak (143 +/- 6 vs. 100 +/- 4 ms in control, P < 0.001) and the time to half relaxation (124 +/- 6 vs. 75 +/- 6 ms in control, P < 0.001). Increased pacing frequency increased contractile force threefold in control myocardium (P < 0.001) but caused no increase of force in Ro1-expressing myocardium. When stimulation was interrupted with rests, postrest force increased in control myocardium, but there was postrest decay of force in Ro1-expressing myocardium. These results suggest that defects in contractility mediated by G(i) signaling may contribute to the development of dilated cardiomyopathy.
Department of Radiology, University of California, San Francisco, California 94143, USA. ajbaker@itsa.ucsf.edu
A J
AJ
Baker
C H
CH
Redfern
M D
MD
Harwood
P C
PC
Simpson
B R
BR
Conklin
D000818:Animals; D002118:Calcium / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D010210:Papillary Muscles / Q000502:physiology / Q000503:physiopathology*; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D017473:Receptors, Opioid, kappa; C110260:Ro1 protein, synthetic; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium