Modeling Na⁺-Ca²⁺ exchange in the heart: Allosteric activation, spatial localization, sparks and...

The cardiac sodium (Na⁺)/calcium (Ca²⁺) exchanger (NCX1) is an electrogenic membrane transporter that regulates Ca²⁺ homeostasis in cardiomyocytes, serving mainly to extrude Ca²⁺ during diastole. The direction of Ca²⁺ transport reverses at membrane potentials near that of the action potential plateau, generating an influx of Ca²⁺ into the cell. Therefore, there has been great interest in the possible roles of NCX1 in cardiac Ca²⁺-induced Ca²⁺ 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 Ca²⁺-dependent allosteric regulation. This NCX1 model was incorporated into a previously developed super-resolution model of the Ca²⁺ 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 Ca²⁺ channels and RyR2s, and that accounts for local Ca²⁺ 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 Ca²⁺ levels. Spark amplitude and duration are less sensitive to NCX1 spatial redistribution. On the other hand, NCX1 plays an important role in promoting Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ during diastole.