title: Modeling Na+-Ca2+exchange in the heart: Allosteric activation, spatial localization, sparks and excitation-contraction coupling.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD, 21218, USA. Electronic address: lchu4@jhu.edu.
authors.forename: Lulu
authors.initials: L
authors.lastname: Chu
authors.affiliation: Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD, 21218, USA. Electronic address: jgreenst@jhu.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Greenstein
authors.affiliation: Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD, 21218, USA. Electronic address: rwinslow@jhu.edu.
authors.forename: Raimond L
authors.initials: RL
authors.lastname: Winslow
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D000494:Allosteric Regulation; D000818:Animals; D020013:Calcium Signaling; D004285:Dogs; D056966:Excitation Contraction Coupling; D015640:Ion Channel Gating; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019831:Sodium-Calcium Exchanger; D012964:Sodium
keywords: Calcium micro-domains; Calcium sparks; Cardiac myocyte; Computational model; Sodium-calcium exchanger; Spark fidelity; Spark rate