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Voltage-Gated Sodium Channel ? Subunits and Their Related Diseases.

ABSTRACT: Voltage-gated sodium channels are protein complexes comprised of one pore forming ? subunit and two, non-pore forming, ? subunits. The voltage-gated sodium channel ? subunits were originally identified to function as auxiliary subunits, which modulate the gating, kinetics, and localization of the ion channel pore. Since that time, the five ? subunits have been shown to play crucial roles as multifunctional signaling molecules involved in cell adhesion, cell migration, neuronal pathfinding, fasciculation, and neurite outgrowth. Here, we provide an overview of the evidence implicating the ? subunits in their conducting and non-conducting roles. Mutations in the ? subunit genes (SCN1B-SCN4B) have been linked to a variety of diseases. These include cancer, epilepsy, cardiac arrhythmias, sudden infant death syndrome/sudden unexpected death in epilepsy, neuropathic pain, and multiple neurodegenerative disorders. ? subunits thus provide novel therapeutic targets for future drug discovery.

SUBMITTER: Bouza AA

PROVIDER: S-EPMC6338345 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Voltage-Gated Sodium Channel β Subunits and Their Related Diseases.

Bouza Alexandra A AA Isom Lori L LL

Handbook of experimental pharmacology 20180101

Voltage-gated sodium channels are protein complexes comprised of one pore forming α subunit and two, non-pore forming, β subunits. The voltage-gated sodium channel β subunits were originally identified to function as auxiliary subunits, which modulate the gating, kinetics, and localization of the ion channel pore. Since that time, the five β subunits have been shown to play crucial roles as multifunctional signaling molecules involved in cell adhesion, cell migration, neuronal pathfinding, fasci ...[more]

PMID: 28965169

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Project description:Background:Voltage-gated sodium (NaV) channels are heteromeric proteins consisting of a single pore forming ?-subunit associated with one or two auxiliary ?-subunits. These channels are classically known for being responsible of action potential generation and propagation in excitable cells; but lately they have been reported as widely expressed and regulated in several human cancer types. We have previously demonstrated the overexpression of NaV1.6 channel in cervical cancer (CeCa) biopsies and primary cultures, and its contribution to cell migration and invasiveness. Here, we investigated the expression of NaV channels ?-subunits (NaV?s) in the CeCa cell lines HeLa, SiHa and CaSki, and determined their contribution to cell proliferation, migration and invasiveness. Methods:We assessed the expression of NaV?s in CeCa cell lines by performing RT-PCR and western blotting experiments. We also evaluated CeCa cell lines proliferation, migration, and invasion by in vitro assays, both in basal conditions and after inducing changes in NaV?s levels by transfecting specific cDNAs or siRNAs. The potential role of NaV?s in modulating the expression of NaV ?-subunits in the plasma membrane of CeCa cells was examined by the patch-clamp whole-cell technique. Furthermore, we investigated the role of NaV?1 on cell cycle in SiHa cells by flow cytometry. Results:We found that the four NaV?s are expressed in the three CeCa cell lines, even in the absence of functional NaV ?-subunit expression in the plasma membrane. Functional in vitro assays showed differential roles for NaV?1 and NaV?4, the latter as a cell invasiveness repressor and the former as a migration abolisher in CeCa cells. In silico analysis of NaV?4 expression in cervical tissues corroborated the downregulation of this protein expression in CeCa vs normal cervix, supporting the evidence of NaV?4's role as a cell invasiveness repressor. Conclusions:Our results contribute to the recent conception about NaV?s as multifunctional proteins involved in cell processes like ion channel regulation, cell adhesion and motility, and even in metastatic cell behaviors. These non-canonical functions of NaV?s are independent of the presence of functional NaV ?-subunits in the plasma membrane and might represent a new therapeutic target for the treatment of cervical cancer.

Dataset Information

Voltage-Gated Sodium Channel ? Subunits and Their Related Diseases.

Publications

Voltage-Gated Sodium Channel β Subunits and Their Related Diseases.

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