The role of the Na+/Ca2+ exchangers in Ca2+ dynamics in ventricular myocytes

The role of the Na+/Ca2+ exchanger (NCX) as the main pathway for Ca2+ extrusion from ventricular myocytes is well established. However, both the role of the Ca2+ entry mode of NCX in regulating local Ca2+ dynamics and the role of the Ca2+ exit mode during the majority of the physiological action potential (AP) are subjects of controversy. The functional significance of NCXs location in T-tubules and potential co-localization with ryanodine receptors was examined using a local Ca2+ control model of low computational cost. Our simulations demonstrate that under physiological conditions local Ca2+ and Na+ gradients are critical in calculating the driving force for NCX and hence in predicting the effect of NCX on AP. Under physiological conditions when 60% of NCXs are located on T-tubules, NCX may be transiently inward within the first 100 ms of an AP and then transiently outward during the AP plateau phase. Thus, during an AP NCX current (INCX) has three reversal points rather than just one. This provides a resolution to experimental observations where Ca2+ entry via NCX during an AP is inconsistent with the time at which INCX is thought to become inward. A more complex than previously believed dynamic regulation of INCX during AP under physiological conditions allows us to interpret apparently contradictory experimental data in a consistent conceptual framework. Our modelling results support the claim that NCX regulates the local control of Ca2+ and provide a powerful tool for future investigations of the control of sarcoplasmic reticulum (SR) Ca2+ release under pathological conditions.