Modulation of cardiac Ca2+ channels by isoproterenol studied in transgenic mice with altered SR Ca2+ content.
Phospholamban (PLB) ablation is associated with enhanced sarcoplasmic reticulum (SR) Ca2+ uptake and attenuation of the cardiac contractile responses to beta-adrenergic agonists. In the present study, we compared the effects of isoproterenol (Iso) on the Ca2+ currents (ICa) of ventricular myocytes isolated from wild-type (WT) and PLB knockout (PLB-KO) mice. Current density and voltage dependence of ICa were similar between WT and PLB-KO cells. However, ICa recorded from PLB-KO myocytes had significantly faster decay kinetics. Iso increased ICa amplitude in both groups in a dose-dependent manner (50% effective concentration, 57.1 nM). Iso did not alter the rate of ICa inactivation in WT cells but significantly prolonged the rate of inactivation in PLB-KO cells. When Ba2+ was used as the charge carrier, Iso slowed the decay of the current in both WT and PLB-KO cells. Depletion of SR Ca2+ by ryanodine also slowed the rate of inactivation of ICa, and subsequent application of Iso further reduced the inactivation rate of both groups. These results suggest that enhanced Ca2+ release from the SR offsets the slowing effects of beta-adrenergic receptor stimulation on the rate of inactivation of ICa.
Sako
H
H
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Ohio 45267, USA.
Green
S A
SA
Kranias
E G
EG
Yatani
A
A
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D000099211:Phospholamban
D000251:Adenosine Triphosphatases; D002118:Calcium; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D012433:Ryanodine; D000099211:Phospholamban