L-type Ca2+ channel recovery from inactivation in rabbit atrial myocytes

Abstract

Adaptation of the myocardium to varying workloads critically depends on the recovery from inactivation (RFI) of L-type Ca²⁺ channels (LCCs) which provide the trigger for cardiac contraction. The goal of the present study was a comprehensive investigation of LCC RFI in atrial myocytes. The study was performed on voltage-clamped rabbit atrial myocytes using a double pulse protocol with variable diastolic intervals in cells held at physiological holding potentials, with intact intracellular Ca²⁺ release, and preserved Na⁺ current and Na⁺ /Ca²⁺ exchanger (NCX) activity. We demonstrate that the kinetics of RFI of LCCs are co-regulated by several factors including resting membrane potential, [Ca²⁺ ]_i , Na⁺ influx, and activity of CaMKII. In addition, activation of CaMKII resulted in increased I_Ca amplitude at higher pacing rates. Pharmacological inhibition of NCX failed to have any significant effect on RFI, indicating that impaired removal of Ca²⁺ by NCX has little effect on LCC recovery. Finally, RFI of intracellular Ca²⁺ release was substantially slower than LCC RFI, suggesting that inactivation kinetics of LCC do not significantly contribute to the beat-to-beat refractoriness of SR Ca²⁺ release. The study demonstrates that CaMKII and intracellular Ca²⁺ dynamics play a central role in modulation of LCC activity in atrial myocytes during increased workloads that could have important consequences under pathological conditions such as atrial fibrillations, where Ca²⁺ cycling and CaMKII activity are altered.

Keywords: Ca2+ channel; Ca2+ cycling; Ca2+/calmodulin-dependent kinase II; atria; recovery from inactivation.