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

Glenn T. Lines ^*, Jørn B. Sande ^* , William E. Louch , Halvor K. Mørk , Per Grøttum  and Ole M. Sejersted 

^* Simula Research Laboratory, Lysaker, Norway; and Institute for Experimental Medical Research, Ullevaal University Hospital and Center for Heart Failure Research, and Section of Medical Informatics, University of Oslo, Oslo, Norway

Correspondence: Address reprint requests to G. T. Lines, E-mail:glennli{at}simula.no.

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 (I_Ca). 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.

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