A novel mechanistic model is formulated for dynamic Ca^2 +-dependent allosteric regulation of NCX1.

The NCX1 model is incorporated into both a super-resolution model of Ca^2 + spark generation and a stochastic ventricular myocyte model.

Results in both models predict that Ca^2 + spark frequency decreases with increasing dyad and/or peri-dyad NCX1 localization.

Whole-cell modeling results are quantitatively consistent with recent imaging data indicating t-tubule NCX1 localization levels.

NCX1 promotes Ca^2 + entry across the sarcolemma into the dyad at depolarized V_m and in the presence of elevated local [Na⁺].