Nernst-Planck-Gaussian finite element modelling of Ca electrodiffusion in amphibian striated muscle transverse tubule-sarcoplasmic reticular triadic junctional domains.

INTRODUCTION

Intracellular Ca signalling regulates membrane permeabilities, enzyme activity, and gene transcription amongst other functions. Large transmembrane Ca electrochemical gradients and low diffusibility between cell compartments potentially generate short-lived, localised, high-[Ca] microdomains. The highest concentration domains likely form between closely apposed membranes, as at amphibian skeletal muscle transverse tubule-sarcoplasmic reticular (T-SR, triad) junctions.

MATERIALS AND METHODS

Finite element computational analysis characterised the formation and steady state and kinetic properties of the Ca microdomains using established empirical physiological and anatomical values. It progressively incorporated Fick diffusion and Nernst-Planck electrodiffusion gradients, K, Cl, and Donnan protein, and calmodulin (CaM)-mediated Ca buffering. It solved for temporal-spatial patterns of free and buffered Ca, Gaussian charge differences, and membrane potential changes, following Ca release into the T-SR junction.

RESULTS

Computational runs using established low and high Ca diffusibility ( ) limits both showed that voltages arising from intracytosolic total [Ca] gradients and the counterions little affected microdomain formation, although elevated reduced attained [Ca] and facilitated its kinetics. Contrastingly, adopting known cytosolic CaM concentrations and CaM-Ca affinities markedly increased steady-state free ([Ca]) and total ([Ca]), albeit slowing microdomain formation, all to extents reduced by high . However, both low and high yielded predictions of similar, physiologically effective, [Ca-CaM]. This Ca trapping by the relatively immobile CaM particularly increased [Ca] at the junction centre. [Ca], [Ca-CaM], [Ca], and microdomain kinetics all depended on both CaM-Ca affinity and These changes accompanied only small Gaussian (∼6 mV) and surface charge (∼1 mV) effects on tubular transmembrane potential at either .

CONCLUSION

These physical predictions of T-SR Ca microdomain formation and properties are compatible with the microdomain roles in Ca and Ca-CaM-mediated signalling but limited the effects on tubular transmembrane potentials. CaM emerges as a potential major regulator of both the kinetics and the extent of microdomain formation. These possible cellular Ca signalling roles are discussed in relation to possible feedback modulation processes sensitive to the μM domain but not nM bulk cytosolic, [Ca], and [Ca-CaM], including ryanodine receptor-mediated SR Ca release; Na, K, and Cl channel-mediated membrane excitation and stabilisation; and Na/Ca exchange transport.