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XB-ART-1025
Eur J Pharmacol 2005 Dec 28;5281-3:17-26. doi: 10.1016/j.ejphar.2005.10.069.
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A mutation in the local anaesthetic binding site abolishes toluene effects in sodium channels.

Gauthereau MY , Salinas-Stefanon EM , Cruz SL .


Abstract
Toluene is a solvent of abuse that inhibits cardiac sodium channels in a manner that resembles the action of local anaesthetics. The purpose of this work was to analyze toluene effects on skeletal muscle sodium channels with and without beta1 subunit (Nav1.4+beta1 and Nav1.4-beta1, respectively) expressed in Xenopus laevis oocytes and to compare them with those produced in the F1579A mutant channel lacking a local anaesthetic binding site. Toluene inhibited Nav1.4 sodium currents (IC50=2.7 mM in Nav1.4+beta1 and 2.2 mM in Nav1.4-beta1 in a concentration dependent way. Toluene (3 mM) blocked sodium currents in Nav1.4 channels proportionally throughout the entire current-voltage relationship producing inactivation at more negative potentials. Minimal inhibition was produced by 3 mM toluene in F1579A mutant channels. Recovery from inactivation was slower both in Nav1.4 and F1579A channels in the presence of 3 mM toluene. The solvent blocked sodium currents in a use-dependent and frequency-dependent manner in Nav1.4 channels. A single mutation in the local anaesthetic binding site of Nav1.4 channels almost abolished toluene effects. These results suggest that this site is important for toluene action.

PubMed ID: 16316648
Article link: Eur J Pharmacol


Species referenced: Xenopus laevis
Genes referenced: nav1 scn4a