Contribution of the Na+/Ca2+ Exchanger to Rapid Ca2+ Release in Cardiomyocytes

Trigger Ca2+ is considered to be the Ca2+ current through the L-type Ca2+ channel (LTCC) that causes release of Ca2+ from the sarcoplasmic reticulum. However, cell contraction also occurs in the absence of the LTCC current (ICa). In this article, we investigate the contribution of the Na+/Ca2+ exchanger (NCX) to the trigger Ca2+. Experimental data from rat cardiomyocytes using confocal microscopy indicating that inhibition of reverse mode Na+/Ca2+ exchange delays the Ca2+ transient by 3–4 ms served as a basis for the mathematical model. A detailed computational model of the dyadic cleft (fuzzy space) is presented where the diffusion of both Na+ and Ca2+ is taken into account. Ionic channels are included at discrete locations, making it possible to study the effect of channel position and colocalization. The simulations indicate that if a Na+ channel is present in the fuzzy space, the NCX is able to bring enough Ca2+ into the cell to affect the timing of release. However, this critically depends on channel placement and local diffusion properties. With fuzzy space diffusion in the order of four orders of magnitude lower than in water, triggering through LTCC alone was up to 5 ms slower than with the presence of a Na+ channel and NCX.