Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domains
IntroductionIntracellular Ca2+ signalling regulates membrane permeabilities, enzyme activity, and gene transcription amongst other functions. Large transmembrane Ca2+ electrochemical gradients and low diffusibility between cell compartments potentially generate short-lived, localised, high-[Ca2+] mi...
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Frontiers Media S.A.
2024-12-01
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| author | Marco D. Rodríguez Joshua A. Morris Oliver J. Bardsley Hugh R. Matthews Christopher L.-H. Huang Christopher L.-H. Huang |
| author_facet | Marco D. Rodríguez Joshua A. Morris Oliver J. Bardsley Hugh R. Matthews Christopher L.-H. Huang Christopher L.-H. Huang |
| author_sort | Marco D. Rodríguez |
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| description | IntroductionIntracellular Ca2+ signalling regulates membrane permeabilities, enzyme activity, and gene transcription amongst other functions. Large transmembrane Ca2+ electrochemical gradients and low diffusibility between cell compartments potentially generate short-lived, localised, high-[Ca2+] 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 methodsFinite element computational analysis characterised the formation and steady state and kinetic properties of the Ca2+ 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 Ca2+ buffering. It solved for temporal–spatial patterns of free and buffered Ca2+, Gaussian charge differences, and membrane potential changes, following Ca2+ release into the T-SR junction.ResultsComputational runs using established low and high Ca2+ diffusibility (DCa2+) limits both showed that voltages arising from intracytosolic total [Ca2+] gradients and the counterions little affected microdomain formation, although elevated DCa2+ reduced attained [Ca2+] and facilitated its kinetics. Contrastingly, adopting known cytosolic CaM concentrations and CaM-Ca2+ affinities markedly increased steady-state free ([Ca2+]free) and total ([Ca2+]), albeit slowing microdomain formation, all to extents reduced by high DCa2+. However, both low and high DCa2+ yielded predictions of similar, physiologically effective, [Ca2+-CaM]. This Ca2+ trapping by the relatively immobile CaM particularly increased [Ca2+] at the junction centre. [Ca2+]free, [Ca2+-CaM], [Ca2+], and microdomain kinetics all depended on both CaM-Ca2+ affinity and DCa2+. These changes accompanied only small Gaussian (∼6 mV) and surface charge (∼1 mV) effects on tubular transmembrane potential at either DCa2+.ConclusionThese physical predictions of T-SR Ca2+ microdomain formation and properties are compatible with the microdomain roles in Ca2+ and Ca2+-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 Ca2+ signalling roles are discussed in relation to possible feedback modulation processes sensitive to the μM domain but not nM bulk cytosolic, [Ca2+]free, and [Ca2+-CaM], including ryanodine receptor-mediated SR Ca2+ release; Na+, K+, and Cl− channel-mediated membrane excitation and stabilisation; and Na+/Ca2+ exchange transport. |
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| spelling | doaj-art-b78daecc1a2e4b8fb46ef6bf2d6f1c382024-12-05T06:28:55ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2024-12-011510.3389/fphys.2024.14683331468333Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domainsMarco D. Rodríguez0Joshua A. Morris1Oliver J. Bardsley2Hugh R. Matthews3Christopher L.-H. Huang4Christopher L.-H. Huang5Physiological Laboratory, University of Cambridge, Cambridge, United KingdomPhysiological Laboratory, University of Cambridge, Cambridge, United KingdomDepartment of Veterinary Medicine, University of Cambridge, Cambridge, United KingdomPhysiological Laboratory, University of Cambridge, Cambridge, United KingdomPhysiological Laboratory, University of Cambridge, Cambridge, United KingdomDepartment of Biochemistry, University of Cambridge, Cambridge, United KingdomIntroductionIntracellular Ca2+ signalling regulates membrane permeabilities, enzyme activity, and gene transcription amongst other functions. Large transmembrane Ca2+ electrochemical gradients and low diffusibility between cell compartments potentially generate short-lived, localised, high-[Ca2+] 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 methodsFinite element computational analysis characterised the formation and steady state and kinetic properties of the Ca2+ 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 Ca2+ buffering. It solved for temporal–spatial patterns of free and buffered Ca2+, Gaussian charge differences, and membrane potential changes, following Ca2+ release into the T-SR junction.ResultsComputational runs using established low and high Ca2+ diffusibility (DCa2+) limits both showed that voltages arising from intracytosolic total [Ca2+] gradients and the counterions little affected microdomain formation, although elevated DCa2+ reduced attained [Ca2+] and facilitated its kinetics. Contrastingly, adopting known cytosolic CaM concentrations and CaM-Ca2+ affinities markedly increased steady-state free ([Ca2+]free) and total ([Ca2+]), albeit slowing microdomain formation, all to extents reduced by high DCa2+. However, both low and high DCa2+ yielded predictions of similar, physiologically effective, [Ca2+-CaM]. This Ca2+ trapping by the relatively immobile CaM particularly increased [Ca2+] at the junction centre. [Ca2+]free, [Ca2+-CaM], [Ca2+], and microdomain kinetics all depended on both CaM-Ca2+ affinity and DCa2+. These changes accompanied only small Gaussian (∼6 mV) and surface charge (∼1 mV) effects on tubular transmembrane potential at either DCa2+.ConclusionThese physical predictions of T-SR Ca2+ microdomain formation and properties are compatible with the microdomain roles in Ca2+ and Ca2+-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 Ca2+ signalling roles are discussed in relation to possible feedback modulation processes sensitive to the μM domain but not nM bulk cytosolic, [Ca2+]free, and [Ca2+-CaM], including ryanodine receptor-mediated SR Ca2+ release; Na+, K+, and Cl− channel-mediated membrane excitation and stabilisation; and Na+/Ca2+ exchange transport.https://www.frontiersin.org/articles/10.3389/fphys.2024.1468333/fullskeletal muscleexcitation–contraction couplingtriad junctioncalcium microdomainsNernst–Planck equationelectrodiffusion |
| spellingShingle | Marco D. Rodríguez Joshua A. Morris Oliver J. Bardsley Hugh R. Matthews Christopher L.-H. Huang Christopher L.-H. Huang Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domains Frontiers in Physiology skeletal muscle excitation–contraction coupling triad junction calcium microdomains Nernst–Planck equation electrodiffusion |
| title | Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domains |
| title_full | Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domains |
| title_fullStr | Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domains |
| title_full_unstemmed | Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domains |
| title_short | Nernst–Planck–Gaussian finite element modelling of Ca2+ electrodiffusion in amphibian striated muscle transverse tubule–sarcoplasmic reticular triadic junctional domains |
| title_sort | nernst planck gaussian finite element modelling of ca2 electrodiffusion in amphibian striated muscle transverse tubule sarcoplasmic reticular triadic junctional domains |
| topic | skeletal muscle excitation–contraction coupling triad junction calcium microdomains Nernst–Planck equation electrodiffusion |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2024.1468333/full |
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