Voltage-gated sodium channels and pain-related disorders

Voltage-gated sodium channels (VGSCs) are heteromeric transmembrane protein complexes. Nine homologous members, SCN1A–11A, make up the VGSC gene family. Sodium channel isoforms display a wide range of kinetic properties endowing different neuronal types with distinctly varied firing properties. Among the VGSCs isoforms, Nav1.7, Nav1.8 and Nav1.9 are preferentially expressed in the peripheral nervous system. These isoforms are known to be crucial in the conduction of nociceptive stimuli with mutations in these channels thought to be the underlying cause of a variety of heritable pain disorders. This review provides an overview of the current literature concerning the role of VGSCs in the generation of pain and heritable pain disorders.

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Mining the Virgin Land of Neurotoxicology: A Novel Paradigm of Neurotoxic Peptides Action on Glycosylated Voltage-Gated Sodium Channels

Journal of Toxicology ◽

10.1155/2012/843787 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Zhirui Liu ◽

Jie Tao ◽

Pin Ye ◽

Yonghua Ji

Keyword(s):

Sodium Channels ◽

Network Activity ◽

Voltage Gated ◽

Virgin Land ◽

Neuronal Network Activity ◽

Voltage Gated Sodium Channels ◽

Pharmacological Targets ◽

Underlying Mechanisms ◽

Posttranslation Modification

Voltage-gated sodium channels (VGSCs) are important membrane protein carrying on the molecular basis for action potentials (AP) in neuronal firings. Even though the structure-function studies were the most pursued spots, the posttranslation modification processes, such as glycosylation, phosphorylation, and alternative splicing associating with channel functions captured less eyesights. The accumulative research suggested an interaction between the sialic acids chains and ion-permeable pores, giving rise to subtle but significant impacts on channel gating. Sodium channel-specific neurotoxic toxins, a family of long-chain polypeptides originated from venomous animals, are found to potentially share the binding sites adjacent to glycosylated region on VGSCs. Thus, an interaction between toxin and glycosylated VGSC might hopefully join the campaign to approach the role of glycosylation in modulating VGSCs-involved neuronal network activity. This paper will cover the state-of-the-art advances of researches on glycosylation-mediated VGSCs function and the possible underlying mechanisms of interactions between toxin and glycosylated VGSCs, which may therefore, fulfill the knowledge in identifying the pharmacological targets and therapeutic values of VGSCs.

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The Role of Nonprotein Domains in the Function and Synthesis of Voltage-Gated Sodium Channels

Ion Channels ◽

10.1007/978-1-4615-7305-0_2 ◽

1990 ◽

pp. 33-64 ◽

Cited By ~ 5

Author(s):

S. R. Levinson ◽

W. B. Thornhill ◽

D. S. Duch ◽

E. Recio-Pinto ◽

B. W. Urban

Keyword(s):

Sodium Channels ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Role of nuclear factor‐kappa B in mitochondria‐derived superoxide‐lowered protein expression of voltage‐gated sodium channels in nodose neurons from heart failure rats

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.703.2 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Huiyin Tu ◽

Jinxu Liu ◽

Yu-long Li

Keyword(s):

Heart Failure ◽

Protein Expression ◽

Sodium Channels ◽

Nuclear Factor Kappa B ◽

Nuclear Factor ◽

Voltage Gated ◽

Nuclear Factor Kappa ◽

Voltage Gated Sodium Channels

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The Emerging Role of Voltage-Gated Sodium Channels in Tumor Biology

Frontiers in Oncology ◽

10.3389/fonc.2019.00124 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Weijia Mao ◽

Jie Zhang ◽

Heinrich Körner ◽

Yong Jiang ◽

Songcheng Ying

Keyword(s):

Sodium Channels ◽

Tumor Biology ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Neuropathic Pain Develops Normally in Mice Lacking both Nav1.7 and Nav1.8

Molecular Pain ◽

10.1186/1744-8069-1-24 ◽

2005 ◽

Vol 1 ◽

pp. 1744-8069-1-24 ◽

Cited By ~ 121

Author(s):

Mohammed A Nassar ◽

Alessandra Levato ◽

L Caroline Stirling ◽

John N Wood

Keyword(s):

Neuropathic Pain ◽

Sodium Channels ◽

Sensory Neurons ◽

Inflammatory Pain ◽

Pain Thresholds ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Pain Symptoms ◽

Α Subunits

Two voltage gated sodium channel α-subunits, Nav1.7 and Nav1.8, are expressed at high levels in nociceptor terminals and have been implicated in the development of inflammatory pain. Mis-expression of voltage-gated sodium channels by damaged sensory neurons has also been implicated in the development of neuropathic pain, but the role of Nav1.7 and Nav1.8 is uncertain. Here we show that deleting Nav1.7 has no effect on the development of neuropathic pain. Double knockouts of both Nav1.7 and Nav1.8 also develop normal levels of neuropathic pain, despite a lack of inflammatory pain symptoms and altered mechanical and thermal acute pain thresholds. These studies demonstrate that, in contrast to the highly significant role for Nav1.7 in determining inflammatory pain thresholds, the development of neuropathic pain does not require the presence of either Nav1.7 or Nav1.8 alone or in combination.

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Role of submembranous actin cytoskeleton in regulation of non-voltage-gated sodium channels

Doklady Biochemistry and Biophysics ◽

10.1134/s1607672913030010 ◽

2013 ◽

Vol 450 (1) ◽

pp. 126-129

Author(s):

V. I. Chubinskiy-Nadezhdin ◽

A. V. Sudarikova ◽

N. N. Nikolsky ◽

E. A. Morachevskaya

Keyword(s):

Actin Cytoskeleton ◽

Sodium Channels ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Differential Effects of Modified Batrachotoxins on Voltage-gated Sodium Channel Fast and Slow Inactivation

10.26434/chemrxiv.14026406.v1 ◽

2021 ◽

Author(s):

Tim M. G. MacKenzie ◽

Fayal Abderemane-Ali ◽

Catherine E. Garrison ◽

Daniel L. Minor Jr. ◽

Justin Du Bois

Keyword(s):

De Novo ◽

Protein Complexes ◽

Transmembrane Protein ◽

Ion Selectivity ◽

Allosteric Modulators ◽

Slow Inactivation ◽

Voltage Gated ◽

Functional Studies ◽

Voltage Gated Sodium Channels ◽

Initiation And Propagation

Voltage-gated sodium channels (NaVs), large transmembrane protein complexes responsible for the initiation and propagation of action potentials, are targets for a number of acute poisons. Many of these agents act as allosteric modulators of channel activity and serve as powerful chemical tools for understanding channel function. Batrachotoxin (BTX) is a steroidal amine derivative most commonly associated with poison dart frogs and is unique as a NaV ligand in that it alters every property of the channel, including threshold potential of activation, inactivation, ion selectivity, and ion conduction. Structure-function studies with BTX are limited, however, by the inability to access preparative quantities of this compound from natural sources. We have addressed this problem through de novo synthesis of BTX, which gives access to modified toxin structures. In this report, we detail electrophysiology studies of three BTX C20-ester derivatives against recombinant NaV subtypes (rat NaV1.4 and human NaV1.5). Two of these compounds, BTX-B and BTX-cHx, are functionally equivalent to BTX, hyperpolarizing channel activation and blocking both fast and slow inactivation. BTX-yne—a C20-n-heptynoate ester—is a conspicuous outlier, eliminating fast but not slow inactivation. This unique property qualifies BTX-yne as the first reported NaV modulator that separates inactivation processes. These findings are supported by functional studies with bacterial NaVs (BacNaVs) that lack a fast inactivation gate. The availability of BTX-yne should advance future efforts aimed at understanding NaV gating mechanisms and designing allosteric regulators of NaV activity.

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