Transient inward current, delayed afterdepolarizations, and calmodulin kinase

Cardiac arrhythmias occur in a wide variety of conditions where increased intracellular Ca²⁺ is known to occur, including myocardial ischemia, cardiac glycoside toxicity, congestive heart failure, and excessive prolongation of action potential duration. The multifunctional Ca²⁺/calmodulin dependent protein kinase II (CaM kinase) is an important physiologic target for intracellular Ca²⁺ and regulates key control points for intracellular Ca²⁺ homeostasis, including L-type Ca²⁺ current, release and uptake of Ca²⁺ from the sarcoplasmic reticulum. Since CaM kinase is uniquely positioned to affect Ca²⁺ sensitive ionic currents and resultant arrhythmias, CaM kinase may also be an effective antiarrhythmic drug target. The transient inward current (I_ti) triggers delayed afterdepolarizations, which are a likely cause of Ca²⁺ overload arrhythmias. The identity of I_ti is controversial, but appears to result from different ionic currents depending on the experimental conditions. These currents are likely activated by intracellular Ca²⁺ because I_ti always follows excessive intracellular Ca²⁺ concentrations ([Ca²⁺]_i). The studies from our laboratory indicate that three different [Ca²⁺]_i sensitive currents, which could contribute to I_ti, are present in rabbit ventricular myocytes. These currents are the Na⁺/Ca²⁺ exchanger, the Ca²⁺ activated Cl^- current, and the Ca²⁺ activated non-selective cation current. We also found that I_ti was suppressed by CaM kinase inhibitory peptides in the presence of physiologic solutions. These data support the hypothesis: CaM kinase can augment I_ti during clinically relevant conditions, which are associated with increased [Ca²⁺]_i, and thus act as a proarrhythmic signaling molecule.