Neonatal Na 1.5 channels: pharmacological distinctiveness of a cancer-related voltage-gated sodium channel splice variant.

Background And Purpose: Voltage-gated sodium (Na ) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal splice variant of Na 1.5 (nNa 1.

Cationic Modulation of Voltage-Gated Sodium Channel (Nav1.5): Neonatal Versus Adult Splice Variants-2. Divalent (Cd) and Trivalent (Gd) Ions.

A "neonatal" splice-form of the voltage-gated sodium channel Nav1.5 is functionally expressed in human cancers and potentiates metastatic cell behaviors. Splicing causes the replacement of 7 amino acids, including a negatively charged aspartate in the "adult" Nav1.

Cationic Modulation of Voltage-Gated Sodium Channel (Nav1.5): Neonatal Versus Adult Splice Variants-1. Monovalent (H) Ions.

Voltage-gated sodium channels are functionally expressed in human carcinomas. In breast and colon cancers, the neonatal splice variant of Nav1.5 (nNav1.

Intracellular calcium oscillations in strongly metastatic human breast and prostate cancer cells: control by voltage-gated sodium channel activity.

The possible association of intracellular Ca with metastasis in human cancer cells is poorly understood. We have studied Ca signaling in human prostate and breast cancer cell lines of strongly versus weakly metastatic potential in a comparative approach. Intracellular free Ca was measured using a membrane-permeant fluorescent Ca-indicator dye (Fluo-4 AM) and confocal microscopy.

Persistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease.

A range of experimental and clinical data suggests strongly (i) that metastatic progression in carcinomas is accompanied (maybe even preceded) by upregulation of functional voltage-gated sodium channels (VGSCs) and (ii) that VGSC activity enhances cancer cell invasiveness. First, this review outlines the available in vitro and in vivo evidence for the VGSC expression and its proposed pathophysiological role. Second, we question the mechanism(s) whereby VGSC activity can induce such a cancer-promoting effect.

Oxidative stress in the in vivo DMBA rat model of breast cancer: suppression by a voltage-gated sodium channel inhibitor (RS100642).

Breast cancer (BCa) was induced in vivo in female rats with 7,12-dimethylbenz(a)anthracene (DMBA). Two main questions were addressed. Firstly, would the carcinogenesis be accompanied by oxidative stress as signalled by superoxide dismutase, glutathione peroxidase, malondialdehyde and total nitrate? Secondly, would treating the rats additionally with a blocker of voltage-gated sodium channel (VGSC) activity, shown previously to promote BCa progression, affect the oxidative responses? The DMBA-induced increases in the antioxidant systems were completely blocked by the VGSC inhibitor RS100642, which also significantly prolonged the lifespan.

Estrogen and non-genomic upregulation of voltage-gated Na(+) channel activity in MDA-MB-231 human breast cancer cells: role in adhesion.

External (but not internal) application of beta-estradiol (E2) increased the current amplitude of voltage-gated Na(+) channels (VGSCs) in MDA-MB-231 human breast cancer (BCa) cells. The G-protein activator GTP-gamma-S, by itself, also increased the VGSC current whilst the G-protein inhibitor GDP-beta-S decreased the effect of E2. Expression of GPR30 (a G-protein-coupled estrogen receptor) in MDA-MB-231 cells was confirmed by PCR, Western blot and immunocytochemistry.

Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: clinical potential of neonatal Nav1.5 in breast cancer.

A variety of ion channels have been detected in cancer cells. In particular, upregulation of voltage-gated sodium channels (VGSCs) has been associated pathophysiologically with several strongly metastatic carcinomas. This review emphasises breast cancer.

Alternative splicing of Nav1.5: an electrophysiological comparison of 'neonatal' and 'adult' isoforms and critical involvement of a lysine residue.

In developmentally regulated D1:S3 splicing of Nav1.5, there are 31 nucleotide differences between the 5'-exon ('neonatal') and the 3'-exon ('adult') forms, resulting in 7 amino acid differences in D1:S3-S3/S4 linker. In particular, splicing replaces a conserved negative aspartate residue in the 'adult' with a positive lysine.