CaM kinase augments cardiac L-type Ca2+ current: a cellular mechanism for long Q-T arrhythmias.
Early afterdepolarizations (EAD) caused by L-type Ca2+ current (ICa, L) are thought to initiate long Q-T arrhythmias, but the role of intracellular Ca2+ in these arrhythmias is controversial. Rabbit ventricular myocytes were stimulated with a prolonged EAD-containing action potential-clamp waveform to investigate the role of Ca2+/calmodulin-dependent protein kinase II (CaM kinase) in ICa,L during repolarization. ICa,L was initially augmented, and augmentation was dependent on Ca2+ from the sarcoplasmic reticulum because the augmentation was prevented by ryanodine or thapsigargin. ICa,L augmentation was also dependent on CaM kinase, because it was prevented by dialysis with the inhibitor peptide AC3-I and reconstituted by exogenous constitutively active CaM kinase when Ba2+ was substituted for bath Ca2+. Ultrastructural studies confirmed that endogenous CaM kinase, L-type Ca2+ channels, and ryanodine receptors colocalized near T tubules. EAD induction was significantly reduced in current-clamped cells dialyzed with AC3-I (4/15) compared with cells dialyzed with an inactive control peptide (11/15, P = 0.013). These findings support the hypothesis that EADs are facilitated by CaM kinase.
Wu
Y
Y
Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232-6300, USA.
MacMillan
L B
LB
McNeill
R B
RB
Colbran
R J
RJ
Anderson
M E
ME
D000818:Animals; D001464:Barium / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D004553:Electric Conductivity; D004594:Electrophysiology; D005260:Female; D007425:Intracellular Membranes / Q000378:metabolism; D008133:Long QT Syndrome / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009994:Osmolar Concentration; D020033:Protein Isoforms / Q000502:physiology; D011817:Rabbits
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020033:Protein Isoforms; D001464:Barium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium