Drug action on voltage-gated sodium channels.
Doctoral thesis, UCL (University College London).
Voltage-gated sodium (Nav) channels are therapeutic targets for several disorders affecting humans, including epilepsy, neurodegeneration and neuropathic pain. Typically, drugs treating these conditions exert a use- and voltage-dependent inhibition of Na currents, an action attributed to the stabilisation of the slow inactivated state which is formed during prolonged depolarisation. The binding site has been suggested to reside in the channel pore at a site only accessible from the intracellular environment. What gives different chemicals having this action in common selectivity for certain disorders (e.g. neuroprotection versus epilepsy) remains a mystery. Several channel subtypes exist, with types Nav1.2 and Nav1.6 being major isoforms found in the brain, raising the possibility that different subtypes exhibit differential drug sensitivity. To investigate this issue and explore the site of drug action further, the action of several Nav channel modulators, including lidocaine (a local anaesthetic) and sipatrigine (a neuroprotective agent), were studied on Na currents generated by Nav1.2a and Nav1.6 channels stably expressed in cell lines, and by acutely dissociated native cells, using electrophysiological techniques. The findings indicated that different drugs have some selectivity for particular channel subtypes. In addition, to study the slow inactivated state more selectively, fast inactivation was inhibited chemically. Inhibition of this mechanism altered both normal channel function and drug action. Drug effect during external and internal application to cells was also compared. Seemingly contrary to the current hypothesis of an internal site of action, drugs were more potent following external application, suggesting that their site of action may be different from the putative intracellularly-accessible “local anaesthetic receptor”. These experimental results were tested using a mathematical simulation of drug diffusion during whole-cell voltage-clamped electrophysiological recordings, to determine whether variations in the physicochemical properties of these drugs could explain their different potencies on internal and external application.
|Title:||Drug action on voltage-gated sodium channels|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Wolfson Inst for Biomedical Research|
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