Modeling the Role of NCX in the Regulation of Cardiomyocyte Microdomain Ca2+ Dynamics

Abstract

The sodium (Na+)/calcium (Ca2+) exchanger (NCX) is an electrogenic membrane transporter that mainly serves as a Ca2+ removal mechanism during relaxation and maintains Ca2+ homeostasis in cardiomyocytes. The direction of transport reverses at membrane potentials near action the potential plateau, generating an influx of Ca2+ into the cell. Therefore, there has been great interest in the role NCX plays in cardiac Ca2+-induced Ca2+-release (CICR), with some controversial findings questioning whether NCX has any role at all. A recent super-resolution optical imaging study suggested that ∼17% of NCX co-localize within the domain occupied by ryanodine receptor (RyR) clusters and ∼30% of NCX are within 100nm of the dyad boundary. Therefore, NCX may play a critical role in modulating Ca2+ spark activity and CICR as a result of its spatial distribution in the T-tubule. Here we examine the potential role of NCX using computational modeling. We have developed a novel mechanistic and biophysically-detailed model of NCX that describes both NCX transport kinetics and dynamics of Ca2+-dependent allosteric regulation. We incorporated this new NCX model into a previously developed super-resolution Ca2+ spark model to examine effects of local NCX spatial distribution on properties of Ca2+ sparks. Dyadic NCX reduces spark frequency but has minimal effects on spark amplitude and half-width. Furthermore, we incorporate NCX into a previously developed computational model of the cardiac ventricular myocyte that includes a detailed description of CICR simulated with stochastic gating of L-Type Ca2+ channels and RyRs in the dyad and accounts for local Ca2+ gradients via inclusion of peri-dyadic compartments. We use this model to investigate the role of NCX and its localization on whole-cell Ca2+ dynamics, the Ca2+ levels in the junctional sarcoplasmic reticulum, and APs.