Full-length reviewSodium channels as molecular targets for antiepileptic drugs
Introduction
In their classic experiments of the early 1950s, Hodgkin and Huxley 33, 34, 35, 36used the newly developed voltage-clamp technique to show that a transient, voltage-activated sodium current was responsible for the initial rapid depolarization of the action potential. At the time of the seminal studies of Hodgkin and Huxley, the experimental tools were not available to determine the molecular basis for voltage-dependent sodium currents. Some 40 years later, we know that these transient sodium fluxes are mediated by voltage-gated sodium channels, heteromultimeric membrane proteins that form sodium selective, voltage-gated pores through the plasma membrane 16, 25, 44. It has now been more than a decade since the cloning of the sodium channel from the electric organ of the eel Electrophorus electricus [69]. In the intervening years, our understanding of sodium channel structure and its relationship to channel function has grown enormously.
Brain sodium channels are molecular targets of a number of chemically diverse antiepileptic agents 80, 95. All of these drugs act by inhibiting ionic currents through sodium channels, but the precise mechanism of inhibition is still not entirely understood. Nevertheless, detailed electrophysiological characterization of drug action, along with recent advances in our knowledge of sodium channel structure–function relationships has provided important clues that may facilitate the development of more effective anticonvulsants. In this review, we examine the molecular structure of the brain sodium channel, and we discuss the relationship between sodium channel structure and the mechanism of action of several conventional and newer antiepileptic sodium channel blockers.
Section snippets
Sodium channel structure and function
The sodium channel protein undergoes voltage-dependent changes in conformation that regulate conductance through the channel pore [32](Fig. 1A). At resting membrane potentials, most channels are in closed resting states. In response to membrane depolarization, channels activate within a few hundred microseconds, resulting in sodium flux through the open channel pore, and then convert to non-conducting inactivated states within a few milliseconds (Fig. 1A). Channels almost never open from
Antiepileptic drugs that act on sodium channels
Sodium channels are the likely molecular targets of a number of important antiepileptic agents, including several promising new compounds [80]. These drugs have diverse chemical structures, but their pharmacological profiles share several common characteristics. First, they prevent tonic hindlimb extension in rats and mice in the maximum electroshock seizure test, and they are effective against partial and generalized tonic–clonic seizures in humans. Second, they inhibit sustained repetitive
Concluding remarks
As new antiepileptic drugs are developed on a rational basis rather than from empirical drug screening, our knowledge of the fundamental neuronal mechanisms underlying normal brain function and paroxysmal activity associated with seizures becomes of central importance. Modulation of the activity of voltage- and ligand-gated ion channels is the molecular basis for the action of many antiepileptic drugs. Accordingly, strategies for the rational design of new antiepileptics have targeted ligand-
Acknowledgements
We would like to thank Drs. D. Earl Patton, Lori Isom and Miriam Meisler for their comments on the manuscript.
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