TY - JOUR
T1 - CaM kinase augments cardiac L-type Ca2+ current
T2 - A cellular mechanism for long Q-T arrhythmias
AU - Yuejin, W. U.
AU - Leigh, B.
AU - MacMillan,
AU - Blair McNeill, R.
AU - Colbran, Roger J.
AU - Anderson, Mark E.
PY - 1999/12/1
Y1 - 1999/12/1
N2 - Early afterdepolarizations (BAD) 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. BAD 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. arrhythmia; calcium channels; action potential; long Q-T syndrome; sarcoplasmic reticulum
AB - Early afterdepolarizations (BAD) 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. BAD 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. arrhythmia; calcium channels; action potential; long Q-T syndrome; sarcoplasmic reticulum
UR - http://www.scopus.com/inward/record.url?scp=33746529262&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33746529262&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:33746529262
SN - 0002-9513
VL - 276
SP - H2168-H2178
JO - American Journal of Physiology
JF - American Journal of Physiology
IS - 6 PART 2
ER -