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An Emerging Role for Voltage-Gated Na+ Channels in Cellular Migration: Regulation of Central Nervous System Development and Potentiation of Invasive Cancers

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI

Mustafa B.A. Djamgoz

Neuroscience Solutions to Cancer Research Group, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London, UK

Lori L. Isom

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, lisom{at}umich.edu

Voltage-gated Na⁺ channels (VGSCs) exist as macromolecular complexes containing a pore-forming subunit and one or more β subunits. The VGSC subunit gene family consists of 10 members, which have distinct tissue-specific and developmental expression profiles. So far, four β subunits (β1—β4) and one splice variant of β1 (β1A, also called β1B) have been identified. VGSC β subunits are multifunctional, serving as modulators of channel activity, regulators of channel cell surface expression, and as members of the immunoglobulin superfamily, cell adhesion molecules (CAMs). β subunits are substrates of β-amyloid precursor protein-cleaving enzyme (BACE1) and -secretase, yielding intracellular domains (ICDs) that may further modulate cellular activity via transcription. Recent evidence shows that β1 regulates migration and pathfinding in the developing postnatal CNS in vivo. The and β subunits, together with other components of the VGSC signaling complex, may have dynamic interactive roles depending on cell/tissue type, developmental stage, and pathophysiology. In addition to excitable cells like nerve and muscle, VGSC and β subunits are functionally expressed in cells that are traditionally considered nonexcitable, including glia, vascular endothelial cells, and cancer cells. In particular, the subunits are up-regulated in line with metastatic potential and are proposed to enhance cellular migration and invasion. In contrast to the subunits, β1 is more highly expressed in weakly metastatic cancer cells, and evidence suggests that its expression enhances cellular adhesion. Thus, novel roles are emerging for VGSC and β subunits in regulating migration during normal postnatal development of the CNS as well as during cancer metastasis.

Key Words: Cancer • Development • Migration • Signaling • Voltage-gated Na+ channel

This version was published on December 1, 2008

The Neuroscientist, Vol. 14, No. 6, 571-583 (2008)
DOI: 10.1177/1073858408320293


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