Modeling Na-Ca exchange in the heart: Allosteric activation, spatial localization, sparks and excitation-contraction coupling.

The cardiac sodium (Na)/calcium (Ca) exchanger (NCX1) is an electrogenic membrane transporter that regulates Ca homeostasis in cardiomyocytes, serving mainly to extrude Ca during diastole. The direction of Ca transport reverses at membrane potentials near that of the action potential plateau, generating an influx of Ca into the cell. Therefore, there has been great interest in the possible roles of NCX1 in cardiac Ca-induced Ca 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 ~120nm 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-dependent allosteric regulation. This NCX1 model was incorporated into a previously developed super-resolution model of the Ca 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 channels and RyR2s, and that accounts for local Ca 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 levels. Spark amplitude and duration are less sensitive to NCX1 spatial redistribution. On the other hand, NCX1 plays an important role in promoting Ca 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 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 during diastole.