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Sinoatrial node pacemaker activity requires Ca(2+)/calmodulin-dependent protein kinase II activation
T M Vinogradova1, Y Y Zhou, K Y Bogdanov
1Laboratory of Cardiovascular Sciences, National Institute of Aging, Gerontology Research Center, Baltimore, Md, USA.
Circulation Research
|October 31, 2000
Summary
Calcium/calmodulin-dependent protein kinase II (CaMKII) is essential for heart pacemaker cells. Inhibiting CaMKII stops heartbeats by affecting calcium currents, highlighting its critical role in cardiac rhythm.
Area of Science:
- Cardiology
- Molecular and Cellular Biology
- Biophysics
Background:
- Cardiac beating originates from sinoatrial (SA) node cells' rhythmic excitation.
- Pacemaker activity is crucial for maintaining a regular heart rhythm.
Purpose of the Study:
- To investigate the role of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in SA node pacemaker activity.
- To elucidate the ionic mechanisms underlying CaMKII's influence on cardiac rhythm.
Main Methods:
- Utilized specific CaMKII inhibitors (AIP, KN-93) and inactive analog (KN-92) on rabbit SA node cells.
- Measured L-type Ca(2+) current (I(Ca, L)) using patch-clamp electrophysiology.
- Employed fast (BAPTA) and slow (EGTA) Ca(2+) chelators.
- Performed confocal immunocytochemical imaging to localize active CaMKII.
Main Results:
- CaMKII inhibition dose-dependently reduced SA node cell action potential rate and amplitude, with complete arrest at higher concentrations.
- CaMKII inhibition decreased I(Ca, L) amplitude and altered its inactivation/reactivation kinetics.
- CaMKII activity was localized near the cell membrane and preferentially regulated by local Ca(2+) transients.
Conclusions:
- CaMKII is obligatory for generating cardiac pacemaker action potentials.
- CaMKII regulates cardiac rhythm primarily by modulating L-type Ca(2+) channel function, particularly inactivation and reactivation.
- Local Ca(2+) transients play a critical role in CaMKII-mediated regulation of pacemaker activity.