Sarcoplasmic reticulum Ca(2+) atpase (SERCA) 1a structurally substitutes for SERCA2a in the cardiac sarcoplasmic reticulum and increases cardiac Ca(2+) handling capacity.
Ectopic expression of the sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA) 1a pump in the mouse heart results in a 2.5-fold increase in total SERCA pump level. SERCA1a hearts show increased rates of contraction/relaxation and enhanced Ca(2+) transients; however, the cellular mechanisms underlying altered Ca(2+) handling in SERCA1a transgenic (TG) hearts are unknown. In this study, using confocal microscopy, we demonstrate that SERCA1a protein traffics to the cardiac SR and structurally substitutes for the endogenous SERCA2a isoform. SR Ca(2+) load measurements revealed that TG myocytes have significantly enhanced SR Ca(2+) load. Confocal line-scan images of field-stimulated SR Ca(2+) release showed an increased rate of Ca(2+) removal in TG myocytes. On the other hand, ryanodine receptor binding activity was decreased by approximately 30%. However, TG myocytes had a greater rate of spontaneous ryanodine receptor opening as measured by spark frequency. Whole-cell L-type Ca(2+) current density was reduced by approximately 50%, whereas the time course of inactivation was unchanged in TG myocytes. These studies provide important evidence that SERCA1a can substitute both structurally and functionally for SERCA2a in the heart and that SERCA1a overexpression can be used to enhance SR Ca(2+) transport and cardiac contractility.
Lalli
M J
MJ
Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Yong
J
J
Prasad
V
V
Hashimoto
K
K
Plank
D
D
Babu
G J
GJ
Kirkpatrick
D
D
Walsh
R A
RA
Sussman
M
M
Yatani
A
A
Marbán
E
E
Periasamy
M
M
D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012433:Ryanodine / Q000378:metabolism / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism
D020746:Calcium Channels, L-Type; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; C107836:Tlx2 protein, mouse; D012433:Ryanodine; D002110:Caffeine; D000252:Calcium-Transporting ATPases; D002118:Calcium