Dataset Information

Finite element analysis predicts Ca²⁺ microdomains within tubular-sarcoplasmic reticular junctions of amphibian skeletal muscle.

ABSTRACT: A finite element analysis modelled diffusional generation of steady-state Ca²⁺ microdomains within skeletal muscle transverse (T)-tubular-sarcoplasmic reticular (SR) junctions, sites of ryanodine receptor (RyR)-mediated SR Ca²⁺ release. It used established quantifications of sarcomere and T-SR anatomy (radial diameter [Formula: see text]; axial distance [Formula: see text]). Its boundary SR Ca²⁺ influx densities,[Formula: see text], reflected step impositions of influxes, [Formula: see text] deduced from previously measured Ca²⁺ signals following muscle fibre depolarization. Predicted steady-state T-SR junctional edge [Ca²⁺], [Ca²⁺]_edge, matched reported corresponding experimental cytosolic [Ca²⁺] elevations given diffusional boundary efflux [Formula: see text] established cytosolic Ca²⁺ diffusion coefficients [Formula: see text] and exit length [Formula: see text]. Dependences of predicted [Ca²⁺]_edge upon [Formula: see text] then matched those of experimental [Ca²⁺] upon Ca²⁺ release through their entire test voltage range. The resulting model consistently predicted elevated steady-state T-SR junctional ~ µM-[Ca²⁺] elevations radially declining from maxima at the T-SR junction centre along the entire axial T-SR distance. These [Ca²⁺] heterogeneities persisted through 10⁴- and fivefold, variations in D and w around, and fivefold reductions in d below, control values, and through reported resting muscle cytosolic [Ca²⁺] values, whilst preserving the flux conservation ([Formula: see text] condition, [Formula: see text]. Skeletal muscle thus potentially forms physiologically significant ~ µM-[Ca²⁺] T-SR microdomains that could regulate cytosolic and membrane signalling molecules including calmodulin and RyR, These findings directly fulfil recent experimental predictions invoking such Ca²⁺ microdomains in observed regulatory effects upon Na⁺ channel function, in a mechanism potentially occurring in similar restricted intracellular spaces in other cell types.

SUBMITTER: Bardsley OJ

PROVIDER: S-EPMC8277803 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+ -Ca2+ exchange (NCX) current, leading to delayed after-depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+ , although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage-clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine-induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L-type Ca2+ current, ICa-L , and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi-channels, TRPC1/4/5, L-type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. KEY POINTS: Heart failure is a pro-arrhythmic state and arrhythmias are a major cause of death. At the cellular level, Ca2+ waves resulting in delayed after-depolarisations are a key trigger of arrhythmias. Ca2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca2+ . We investigate the mechanism by which raising external Ca2+ causes waves, and how this is modified in heart failure. We demonstrate that a novel sarcolemmal background Ca2+ influx via the TRPC6 channel is responsible for SR Ca2+ overload and Ca2+ waves. The increased propensity for Ca2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content. The results of the present study highlight a novel mechanism by which Ca2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets.

Dataset Information

Finite element analysis predicts Ca²⁺ microdomains within tubular-sarcoplasmic reticular junctions of amphibian skeletal muscle.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Finite element analysis predicts Ca2+ microdomains within tubular-sarcoplasmic reticular junctions of amphibian skeletal muscle.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Finite element analysis predicts Ca²⁺ microdomains within tubular-sarcoplasmic reticular junctions of amphibian skeletal muscle.