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

Abstract

Trigger Ca(2+) is considered to be the Ca(2+) current through the L-type Ca(2+) channel (LTCC) that causes release of Ca(2+) 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(+)/Ca(2+) exchanger (NCX) to the trigger Ca(2+). Experimental data from rat cardiomyocytes using confocal microscopy indicating that inhibition of reverse mode Na(+)/Ca(2+) exchange delays the Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.

Modelling cardiac calcium sparks in a three‐dimensional reconstruction of a calcium release unit

“…This measurement is a rudimentary proof-of-principle test for how effectively a Ca 2+ wave-front can sensitize the RyRs in the CRU via increased SR Ca 2+ load (Keller et al 2007). The distance between the CRUs in the longitudinal direction was ∼2 μm and with a Ca 2+ wave travelling at 100 μm s −1 (Lamont et al 1998;Ter Keurs & Boyden, 2007) (Trafford et al 1995;Lines et al 2006) NCX exists within the dyad where it would experience a very high local [Ca 2+ ]. We hypothesized that including NCX flux within the dyad would be capable of directly and markedly altering dyadic [Ca 2+ ], and spark dynamics.…”

“…Both computational and experimental studies have also investigated whether NCX can contribute to EC coupling (Lines et al 2006;Larbig et al 2010). Here we used our model to predict the amount of Ca 2+ that can be extruded from the CRU via NCX during a spark.…”

Colocalization of voltage-gated Na+channels with the Na+/Ca2+exchanger in rabbit cardiomyocytes during development

“…One possible source of the reduced Na ϩ mobility is the dyadic cleft itself (42), in which a restricted space reduces the effective diffusional coefficient. In neonatal rabbit myocytes, electron micrographs have identified 300-nm sheets of the SR membrane located ϳ20 nm beneath the sarcolemma (32), which may contribute to reduce Na ϩ mobility.…”

“…Coupling between NCX and RyR at early stages in development may benefit from the presence of ϳ300-nm-wide sheets of the subsarcolemmal SR membrane recently identified in 3-day-old, but not 56-day-old, ventricular myocytes (32) The stoichiometry of NCX transport renders the reversal potential of NCX intensely sensitive to cytosolic Na ϩ concentration, and small changes in global Na ϩ concentration are expected to mediate large changes in I NCX (20). In fact, modeling experiments have reported that a solitary Na ϩ channel could be sufficient to induce reverse-mode NCX in a dyadic cleft if the influx is concomitant with greatly reduced Na ϩ mobility (42). Thus, Na ϩ channels localized within localized clusters of NCX are expected to have important functional consequences.…”

Dofetilide Enhances the Contractility of Rat Ventricular Myocytes via Augmentation of Na+–Ca2+ Exchange

“…The physiological role of NCE is to maintain low intracellular Ca 2+ concentration at rest by extruding excess intracellular Ca 2+ in inward mode after the fast Ca 2+ -induced Ca 2+ release (CICR) process during systole. On the other hand, Ca 2+ influx via the outward mode of NCE may also contribute to the trigger Ca 2+ and may quicken, enhance or even provoke myocytes contraction [7]. Increases in NCX mRNA and protein are common findings in several animal models of heart failure or left ventricular hypertrophy [8][9][10], as well as in similar cardiac disorders in man [11,12].…”