Modeling Na⁺-Ca^{2 +} exchange in the heart: Allosteric activation, spatial localization, sparks and excitation-contraction coupling

The cardiac sodium (Na⁺)/calcium (Ca^{2 +}) exchanger (NCX1) is an electrogenic membrane transporter that regulates Ca^{2 +} homeostasis in cardiomyocytes, serving mainly to extrude Ca^{2 +} during diastole. The direction of Ca^{2 +} transport reverses at membrane potentials near that of the action potential plateau, generating an influx of Ca^{2 +} into the cell. Therefore, there has been great interest in the possible roles of NCX1 in cardiac Ca^{2 +}-induced Ca^{2 +} release (CICR). Interest has been reinvigorated by a recent super-resolution optical imaging study suggesting that ~ 18% of NCX1 co-localize with ryanodine receptor (RyR2) clusters, and ~ 30% of additional NCX1 are localized to within ~ 120 nm of the nearest RyR2. NCX1 may therefore occupy a privileged position in which to modulate CICR. To examine this question, we have developed a mechanistic biophysically-detailed model of NCX1 that describes both NCX1 transport kinetics and Ca^{2 +}-dependent allosteric regulation. This NCX1 model was incorporated into a previously developed super-resolution model of the Ca^{2 +} spark as well as a computational model of the cardiac ventricular myocyte that includes a detailed description of CICR with stochastic gating of L-type Ca^{2 +} channels and RyR2s, and that accounts for local Ca^{2 +} gradients near the dyad via inclusion of a peri-dyadic (PD) compartment. Both models predict that increasing the fraction of NCX1 in the dyad and PD decreases spark frequency, fidelity, and diastolic Ca^{2 +} levels. Spark amplitude and duration are less sensitive to NCX1 spatial redistribution. On the other hand, NCX1 plays an important role in promoting Ca^{2 +} entry into the dyad, and hence contributing to the trigger for RyR2 release at depolarized membrane potentials and in the presence of elevated local Na⁺ concentration. Whole-cell simulation of NCX1 tail currents are consistent with the finding that a relatively high fraction of NCX1 (~ 45%) resides in the dyadic and PD spaces, with a dyad-to-PD ratio of roughly 1:2. Allosteric Ca^{2 +} activation of NCX1 helps to “functionally localize” exchanger activity to the dyad and PD by reducing exchanger activity in the cytosol thereby protecting the cell from excessive loss of Ca^{2 +} during diastole.