Dataset Information

Modeling Ca²⁺-Bound Troponin in Excitation Contraction Coupling.

ABSTRACT: To explain disparate decay rates of cytosolic Ca²⁺ and structural changes in the thin filaments during a twitch, we model the time course of Ca²⁺-bound troponin (Tn) resulting from the free Ca²⁺ transient of fast skeletal muscle. In fibers stretched beyond overlap, the decay of Ca²⁺ as measured by a change in fluo-3 fluorescence is significantly slower than the intensity decay of the meridional 1/38.5 nm^-1 reflection of Tn; this is not simply explained by considering only the Ca²⁺ binding properties of Tn alone (Matsuo et al., 2010). We apply a comprehensive model that includes the known Ca²⁺ binding properties of Tn in the context of the thin filament with and without cycling crossbridges. Calculations based on the model predict that the transient of Ca²⁺-bound Tn correlates with either the fluo-3 time course in muscle with overlapping thin and thick filaments or the intensity of the meridional 1/38.5 nm^-1 reflection in overstretched muscle. Hence, cycling crossbridges delay the dissociation of Ca²⁺ from Tn. Correlation with the fluo-3 fluorescence change is not causal given that the transient of Ca²⁺-bound Tn depends on sarcomere length, whereas the fluo-3 fluorescence change does not. Transient positions of tropomyosin calculated from the time course of Ca²⁺-bound Tn are in reasonable agreement with the transient of measured perturbations of the Tn repeat in overlap and non-overlap muscle preparations.

SUBMITTER: Zot HG

PROVIDER: S-EPMC5030304 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Modeling Ca2+-Bound Troponin in Excitation Contraction Coupling.

Zot Henry G HG Hasbun Javier E JE

Frontiers in physiology 20160921

To explain disparate decay rates of cytosolic Ca2+ and structural changes in the thin filaments during a twitch, we model the time course of Ca2+-bound troponin (Tn) resulting from the free Ca2+ transient of fast skeletal muscle. In fibers stretched beyond overlap, the decay of Ca2+ as measured by a change in fluo-3 fluorescence is significantly slower than the intensity decay of the meridional 1/38.5 nm-1 reflection of Tn; this is not simpl ...[more]

PMID: 27708586

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Project description: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.

Dataset Information

Modeling Ca²⁺-Bound Troponin in Excitation Contraction Coupling.

Publications

Modeling Ca<sup>2+</sup>-Bound Troponin in Excitation Contraction Coupling.

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