Role of the Na+-Ca2+ exchanger as an alternative trigger of CICR in mammalian cardiac myocytes

Ca2+ influx through the L-type Ca2+ Channels is the primary pathway for triggering the Ca2+ release from the sarcoplasmic reticulum (SR). However, several observations have shown that Ca2+ influx via the reverse mode of the Na+-Ca2+ exchanger current (/(Na-Ca)) could also trigger the Ca2+ release. The aim of the present study was to quantitate the role of this alternative pathway of Ca2+ influx using a mathematical model. In our model 20% of the fast sodium channels and the Na+-Ca2+ exchanger molecules are located in the restricted subspace between the sarcolemma and the SR where triggering of the calcium-induced calcium release (CICR) takes place. After determining the strengths of the alternative triggers with simulated voltage-clamps in varied membrane voltages and resting [Na](i) values, we studied the CICR in simulated action potentials, where fast sodium channel current contributes [Na](i) of the subspace. In low initial [Na](i) the Ca2+ influx via the L-type Ca2+ channels is the major trigger for Ca2+ release from the SR, and the Ca2+ influx via the reverse mode of the Na+-Ca2+ exchanger cannot trigger the CICR. However, depending on the initial [Na](i), the contribution of the Ca2+ entry via the exchanger may account for 25% (at [Na](i) = 10 mM) to nearly 100% ([Na](i) = 30 mM) of the trigger Ca2+. The shift of the main trigger from L-type calcium channels to the exchanger reduced the delay between the action potential upstroke and the intracellular calcium transient. This may contribute to the function of the myocyte in physiological situations where [Na], is elevated. These main results remain the same when using different estimates for the most crucial parameters in the modeling or different models for the exchanger.