Calmodulin kinase and L-type calcium channels: A recipe for arrhythmias?

L-type Ca²⁺ channels (LTCCs) are the main portal for Ca ²⁺ entry into cardiac myocytes. These ion channel proteins open in response to cell membrane depolarizations elicited by action potentials, and LTCC current (I_Ca) flows during the action potential plateau, to increase cellular Ca²⁺ (Ca²⁺ _i) and trigger myocardial contraction. I_Ca is also implicated in the genesis of cardiac arrhythmias under conditions such as heart failure and cardiac hypertrophy, in which the action potential plateau and QT interval are prolonged. This article reviews recent findings about the molecular regulation of LTCCs by the Ca²⁺-dependent signaling molecule, calmodulin kinase II (CaMKII), and compares this form of regulation with regulation by calmodulin-binding domains and β-adrenergic receptor agonists. LTCC dysregulation is discussed in the context of new results showing that CaMKII can be a proarrhythmic signal in disease conditions in which Ca²⁺ _i is disordered and cardiac repolarization is excessively prolonged.