Ca2+-dependent modulation of voltage-gated myocyte sodium channels.
Action Potentials
Animals
Binding Sites
Calcium
/ metabolism
Calcium Signaling
Disease Models, Animal
Flecainide
/ therapeutic use
Humans
Ion Channel Gating
Mice
Myocytes, Cardiac
/ metabolism
NAV1.4 Voltage-Gated Sodium Channel
/ metabolism
NAV1.5 Voltage-Gated Sodium Channel
/ metabolism
Ryanodine Receptor Calcium Release Channel
/ genetics
Sodium
/ metabolism
Tachycardia, Ventricular
/ drug therapy
Treatment Outcome
Voltage-Gated Sodium Channel Blockers
/ therapeutic use
C-terminal domain
ca2+
cardiac arrhythmia
cardiomyocytes
skeletal myocytes
sodium channels
Journal
Biochemical Society transactions
ISSN: 1470-8752
Titre abrégé: Biochem Soc Trans
Pays: England
ID NLM: 7506897
Informations de publication
Date de publication:
01 11 2021
01 11 2021
Historique:
received:
08
04
2021
revised:
01
08
2021
accepted:
31
08
2021
pubmed:
14
10
2021
medline:
22
2
2022
entrez:
13
10
2021
Statut:
ppublish
Résumé
Voltage-dependent Na+ channel activation underlies action potential generation fundamental to cellular excitability. In skeletal and cardiac muscle this triggers contraction via ryanodine-receptor (RyR)-mediated sarcoplasmic reticular (SR) Ca2+ release. We here review potential feedback actions of intracellular [Ca2+] ([Ca2+]i) on Na+ channel activity, surveying their structural, genetic and cellular and functional implications, translating these to their possible clinical importance. In addition to phosphorylation sites, both Nav1.4 and Nav1.5 possess potentially regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III-IV linker and C-terminal domains (CTD), where mutations are associated with a range of skeletal and cardiac muscle diseases. We summarize in vitro cell-attached patch clamp studies reporting correspondingly diverse, direct and indirect, Ca2+ effects upon maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) characterizing channel gating, in cellular expression systems and isolated myocytes. Interventions increasing cytoplasmic [Ca2+]i down-regulated Imax leaving V1/2 constant in native loose patch clamped, wild-type murine skeletal and cardiac myocytes. They correspondingly reduced action potential upstroke rates and conduction velocities, causing pro-arrhythmic effects in intact perfused hearts. Genetically modified murine RyR2-P2328S hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT), recapitulated clinical ventricular and atrial pro-arrhythmic phenotypes following catecholaminergic challenge. These accompanied reductions in action potential conduction velocities. The latter were reversed by flecainide at RyR-blocking concentrations specifically in RyR2-P2328S as opposed to wild-type hearts, suggesting a basis for its recent therapeutic application in CPVT. We finally explore the relevance of these mechanisms in further genetic paradigms for commoner metabolic and structural cardiac disease.
Identifiants
pubmed: 34643236
pii: 229928
doi: 10.1042/BST20200604
pmc: PMC8589445
doi:
Substances chimiques
NAV1.4 Voltage-Gated Sodium Channel
0
NAV1.5 Voltage-Gated Sodium Channel
0
Ryanodine Receptor Calcium Release Channel
0
Voltage-Gated Sodium Channel Blockers
0
ryanodine receptor 2. mouse
0
Sodium
9NEZ333N27
Flecainide
K94FTS1806
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1941-1961Subventions
Organisme : British Heart Foundation
ID : PG/19/59/34582
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 105727/Z/14/Z
Pays : United Kingdom
Organisme : Academy of Medical Sciences
ID : MR/M001288/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/14/79/31102
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M001288/1
Pays : United Kingdom
Informations de copyright
© 2021 The Author(s).
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