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Chronic SR Ca2+-ATPase inhibition causes adaptive changes in cellular Ca2+ transport
Angela G Brittsan1, Kenneth S Ginsburg, Guoxiang Chu
1Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, PO Box 670575, Cincinnati, Ohio 45267-0575, USA.
Circulation Research
|March 15, 2003
Summary
Phospholamban phosphorylation is key for beta-adrenergic response in heart cells. Blocking this phosphorylation leads to unique adaptations in calcium handling, partly restoring heart function.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Cellular Biology
Background:
- Phospholamban regulates cardiac SERCA2a Ca2+ affinity and is phosphorylated during beta-adrenergic stimulation.
- Understanding phospholamban's role is crucial for cardiac function and disease.
Purpose of the Study:
- To investigate the impact of nonphosphorylatable phospholamban on cardiac function.
- To elucidate the compensatory mechanisms in response to abolished adrenergic regulation of phospholamban.
Main Methods:
- Generated phospholamban double-mutant (S16A, T17A) mice.
- Utilized in vitro phosphorylation assays and cardiomyocyte studies.
- Measured Ca2+ transients, L-type Ca2+ current (ICa) density, and other Ca2+-handling proteins.
Main Results:
- Nonphosphorylatable phospholamban blocked isoproterenol-induced increases in Ca2+ transient decline rate.
- Increased L-type Ca2+ current (ICa) density was the primary cellular compensation.
- Dynamic ICa modulation partially normalized beta-adrenergic inotropy.
Conclusions:
- Ablation of phospholamban phosphorylation leads to unique cellular adaptations, primarily through enhanced ICa modulation.
- This adaptation partially compensates for impaired SERCA2a responsiveness, normalizing beta-adrenergic inotropy.
Keywords:
Non-programmatic