Modeling Na + -Ca 2+ 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 ~120 nm 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.

Crosslink between calcium and sodium signalling

“…In NCX3, alternative splicing involves only three exons (A, B, and C), whereas both mutually exclusive exons, A and B, are expressed in neurones and glia (Giladi et al , 2015; Chu et al , 2016; Lee et al , 2016; Tal et al , 2016; Giladi et al , 2017). In A-exon-containing NCX1 variants, CBD2 binds two Ca 2+ ions, whereas in B-exon-containing NCX1 variants, CBD2 does not bind Ca 2+ (Giladi et al , 2012).…”

“…Computer-aided modelling reveals NCX can significantly contribute to Ca 2+ -induced Ca 2+ -release (CICR) in cardiomyocytes (Chu et al , 2016), when taking into account experimentally obtained parameters of allosteric regulation of cardiac NCX and high-resolution cell-imaging of subcellular NCX location in cardiomyocyte (Chu et al , 2016). According to this model, increasing the fraction of NCX in the dyad and peri-dyadic (PD) domains decreases frequency and fidelity of Ca 2+ sparks, as well as diastolic [Ca 2+ ] i , although amplitude and duration of Ca 2+ sparks are less sensitive to NCX spatial redistribution.…”

NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes

“…Additionally, we assumed that each CRU in the network has the same number of LTCC and RyRs, thereby neglecting heterogeneities in CRU properties that may be present (40,51) and could potentially affect the distributions of local Ca 2þ spark amplitudes and local NCX currents. Moreover, we have only considered one specific NCX model, and whether similar effects occur with other available NCX models remains to be investigated (52). Finally, we have neglected the spatial variation of Ca 2þ within the submicron dyadic space.…”

Multiple H+ sensors mediate the extracellular acidification-induced [Ca2+]i elevation in cultured rat ventricular cardiomyocytes

“…However, the concrete mechanisms of Ca 2+ transients are diverse and uncertain. Several studies have shown that the increase of [Ca 2+ ] i is induced by the influx of extracellular Ca 2+ via membrane Ca 2+ channels or Na + /Ca 2+ exchangers34. However, the increase of intracellular Ca 2+ also can be resulted from the mobilization of sarcoplasmic reticulum (SR) during acidosis56.…”