Nernst-Planck-Gaussian finite element modelling of Ca 2+ electrodiffusion in amphibian striated muscle transverse tubule-sarcoplasmic reticular triadic junctional domains.

Autor:	Rodríguez MD; Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom., Morris JA; Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom., Bardsley OJ; Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom., Matthews HR; Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom., Huang CL; Physiological Laboratory, University of Cambridge, Cambridge, United Kingdom.; Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2024 Dec 05; Vol. 15, pp. 1468333. Date of Electronic Publication: 2024 Dec 05 (Print Publication: 2024).
DOI:	10.3389/fphys.2024.1468333
Abstrakt:	Introduction: Intracellular Ca ²⁺ signalling regulates membrane permeabilities, enzyme activity, and gene transcription amongst other functions. Large transmembrane Ca ²⁺ electrochemical gradients and low diffusibility between cell compartments potentially generate short-lived, localised, high-[Ca ²⁺ ] 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 ²⁺ 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 ²⁺ buffering. It solved for temporal-spatial patterns of free and buffered Ca ²⁺ , Gaussian charge differences, and membrane potential changes, following Ca ²⁺ release into the T-SR junction. Results: Computational runs using established low and high Ca ²⁺ diffusibility ( D Ca2+ ) limits both showed that voltages arising from intracytosolic total [Ca ²⁺ ] gradients and the counterions little affected microdomain formation, although elevated D Ca2+ reduced attained [Ca ²⁺ ] and facilitated its kinetics. Contrastingly, adopting known cytosolic CaM concentrations and CaM-Ca ²⁺ affinities markedly increased steady-state free ([Ca ²⁺ ] free ) and total ([Ca ²⁺ ]), albeit slowing microdomain formation, all to extents reduced by high D Ca2+ . However, both low and high D Ca2+ yielded predictions of similar, physiologically effective, [Ca ²⁺ -CaM]. This Ca ²⁺ trapping by the relatively immobile CaM particularly increased [Ca ²⁺ ] at the junction centre. [Ca ²⁺ ] free , [Ca ²⁺ -CaM], [Ca ²⁺ ], and microdomain kinetics all depended on both CaM-Ca ²⁺ affinity and D Ca2+. These changes accompanied only small Gaussian (∼6 mV) and surface charge (∼1 mV) effects on tubular transmembrane potential at either D Ca2+ . Conclusion: These physical predictions of T-SR Ca ²⁺ microdomain formation and properties are compatible with the microdomain roles in Ca ²⁺ and Ca ²⁺ -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 ²⁺ signalling roles are discussed in relation to possible feedback modulation processes sensitive to the μM domain but not nM bulk cytosolic, [Ca ²⁺ ] free , and [Ca ²⁺ -CaM], including ryanodine receptor-mediated SR Ca ²⁺ release; Na ⁺ , K ⁺ , and Cl ^- channel-mediated membrane excitation and stabilisation; and Na ⁺ /Ca ²⁺ exchange transport. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Rodríguez, Morris, Bardsley, Matthews and Huang.)
Databáze:	MEDLINE
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