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dc.contributor.authorLiu, Sean X.
dc.contributor.authorMatthews, Hugh R.
dc.contributor.authorHuang, Christopher L.-H.
dc.date.accessioned2021-02-02T17:13:40Z
dc.date.available2021-02-02T17:13:40Z
dc.date.issued2021-02-02
dc.date.submitted2020-09-16
dc.identifier.others41598-021-82493-w
dc.identifier.other82493
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/317015
dc.description.abstractAbstract: Skeletal muscle Na+ channels possess Ca2+- and calmodulin-binding sites implicated in Nav1.4 current (INa) downregulation following ryanodine receptor (RyR1) activation produced by exchange protein directly activated by cyclic AMP or caffeine challenge, effects abrogated by the RyR1-antagonist dantrolene which itself increased INa. These findings were attributed to actions of consequently altered cytosolic Ca2+, [Ca2+]i, on Nav1.4. We extend the latter hypothesis employing cyclopiazonic acid (CPA) challenge, which similarly increases [Ca2+]i, but through contrastingly inhibiting sarcoplasmic reticular (SR) Ca2+-ATPase. Loose patch clamping determined Na+ current (INa) families in intact native murine gastrocnemius skeletal myocytes, minimising artefactual [Ca2+]i perturbations. A bespoke flow system permitted continuous INa comparisons through graded depolarizing steps in identical stable membrane patches before and following solution change. In contrast to the previous studies modifying RyR1 activity, and imposing control solution changes, CPA (0.1 and 1 µM) produced persistent increases in INa within 1–4 min of introduction. CPA pre-treatment additionally abrogated previously reported reductions in INa produced by 0.5 mM caffeine. Plots of peak current against voltage excursion demonstrated that 1 µM CPA increased maximum INa by ~ 30%. It only slightly decreased half-maximal activating voltages (V0.5) and steepness factors (k), by 2 mV and 0.7, in contrast to the V0.5 and k shifts reported with direct RyR1 modification. These paradoxical findings complement previously reported downregulatory effects on Nav1.4 of RyR1-agonist mediated increases in bulk cytosolic [Ca2+]. They implicate possible local tubule-sarcoplasmic triadic domains containing reduced [Ca2+]TSR in the observed upregulation of Nav1.4 function following CPA-induced SR Ca2+ depletion.
dc.languageen
dc.publisherNature Publishing Group UK
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectArticle
dc.subject/631/1647
dc.subject/631/57
dc.subject/631/443
dc.subjectarticle
dc.titleSarcoplasmic reticular Ca 2+ -ATPase inhibition paradoxically upregulates murine skeletal muscle Na v 1.4 function
dc.typeArticle
dc.date.updated2021-02-02T17:13:40Z
prism.issueIdentifier1
prism.publicationNameScientific Reports
prism.volume11
dc.identifier.doi10.17863/CAM.64126
dcterms.dateAccepted2021-01-11
rioxxterms.versionofrecord10.1038/s41598-021-82493-w
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidHuang, Christopher L.-H. [0000-0001-9553-6112]
dc.identifier.eissn2045-2322
pubs.funder-project-idBritish Heart Foundation (PG/14/79/31102, PG/19/59/34582)
pubs.funder-project-idMedical Research Council UK (MR/M001288/1)
pubs.funder-project-idWellcome Trust (105727/Z/14/Z)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)