Contribution of the Na-Ca Exchanger to Rapid Ca Release in Cardiomyocytes

¹ Simula Research Laboratory
² Institute for Experimental Medical Research, Ullevaal University Hospital, University of Oslo
³ Section of Medical Informatics, University of Oslo

^* To whom correspondence should be addressed. E-mail: glennli{at}simula.no.

Submitted on August 11, 2005
Revised on September 6, 2005
Accepted on 21 April 2006

	Abstract

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 (SR). However, cell contraction also occurs in the absence of the LTCC current (I_Ca). In this paper 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 4 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.

Key Words: calcium-induced calcium release, cleft space, mathematical modelling, ryanodine receptors, sodium calcium exchanger

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