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 (I(Ca,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 I(Ca,L) during repolarization. I(Ca,L) was initially augmented, and augmentation was dependent on Ca²⁺ from the sarcoplasmic reticulum because the augmentation was prevented by ryanodine or thapsigargin. I(Ca,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.