Voltage-gated sodium channels

Voltage-gated sodium channels (VGSCs, NaVs) can allow the flow of Na+ ions through cell membrane in response to changes in membrane potential. They play the critical step in fast electrical communication by initiating and propagating action potential firing in central and peripheral neurons, and skeletal and heart muscle. VGSCs go through resting (closed), active (open), and inactive states; as some channels open when there is a change in the cell's membrane potential, Na+ ions will move into the cell down their electrochemical gradient, further depolarizing the cell, and causing more VGSCs to open in a positive feedback loop. Then the closed-inactivated state allows the restoration of local membrane potential, while action potential propagates further along the cell membrane.

VGSCs consist of a large transmembrane α subunits that are functional on their own, and one or two β subunits. At least nine α proteins exist, each encoded by different genes, and distinguished also by their kinetics and tissue specific expression profiles. Mutations in human genes encoding VGSC subtypes have been linked to channelopathies such as epilepsy, cardiac arrhythmias, and chronic pain syndromes. Sodium channel blockers have been developed as anticonvulsants, antiarrhythmic, and local anaesthetic drugs. VGSCs are also the targets of numerous natural neurotoxins such as tetrodotoxin.

[18F]fluorolidocaine

Lidocaine prolongs the inactivation of the VGSCs, and has been used as local anaesthetic and to treat ventricular tachycardia. 18F-labelled lidocaine ([18F]fluorolidocaine, radiocaine) has been developed and, despite its relatively low affinity, it has shown potential to imaging myocardial VGSCs (Hooker et al., 2017) and neuropathic injury (Bartolo et al., 2022).


See also:


Literature

Bean BP. The action potential in mammalian central neurons. Nat Rev Neurosci. 2007; 8(6): 451-465. doi: 10.1038/nrn2148.

de Lera Ruiz M, Kraus RL. Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. J Med Chem. 2015; 58: 7093-7118. doi: 10.1021/jm501981g.

Noreng S, Li T, Payandeh J. Structural pharmacology of voltage-gated sodium channels. J Mol Biol. 2021; 433(17): 166967. doi: 10.1016/j.jmb.2021.166967.



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Updated at: 2023-01-05
Created at: 2023-01-05
Written by: Vesa Oikonen