Local Calcium Dynamics Stabilize NCX Current in an Integrated Calcium Cycling and Membrane Model

Abstract

It has been suggested that Na-Ca exchanger (NCX) plays an important role in pacemaker function as a link between intracellular Ca2+ dynamics and the membrane ion currents. This role remains unresolved due to a lack of specific NCX blockers and the challenges in measuring NCX current (INCX) under different conditions. We approach the problem via a new model that combines a model of SA node cells featuring local Ca2+ control with the entire ensemble of ion currents described by an earlier Maltsev-Lakatta common pool model in order to simulate pacemaker potentials. This approach discovered a new mechanism of stabilization of the INCX using local calcium dynamics when the number of NCX molecules is decreased (as for example in an incomplete NCX knock-out). In this model, during the diastolic depolarization, the Ca2+ released via a ryanodine receptor (RyR) in the sarcoplasmic reticulum in SANC can recruit its neighboring RyRs to release more Ca2+. The extent of this local RyR recruitment depends upon the extent to which the released Ca2+ diffuses and interacts with neighboring RyRs. As the NCX steals Ca2+ in the vicinity of each RyR, it restrains C2+a induced Ca2+ release. This restraint wanes as NCX expression becomes reduced, ensuring that INCX remains almost unchanged. We furthermore examine when this stabilization mechanism becomes saturated, and find that saturation occurs when all RyRs open to release Ca2+. This leads to arrhythmias and pacemaker failure. Comparing our results to earlier common-pool models we find that only ours predicts physiological Ca2+ levels as NCX expression is reduced. Thus our simulations discovered a new INCX stabilization mechanism in cardiac pacemaker cells via local Ca2+ control.