Molecular targets for antiepileptic drug development

Brian S Meldrum; Michael A Rogawski

doi:10.1016/j.nurt.2006.11.010

. 2007 Jan;4(1):18–61. doi: 10.1016/j.nurt.2006.11.010

Molecular targets for antiepileptic drug development

Brian S Meldrum ¹, Michael A Rogawski ^2,^✉

PMCID: PMC1852436 NIHMSID: NIHMS19447 PMID: 17199015

Summary

This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the α subunits of voltage-gated Na⁺ channels and also T-type voltage-gated Ca²⁺ channels) or influence GABA-mediated inhibition. Recently, α2-δ voltage-gated Ca²⁺ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na⁺ channels and GABA_A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca²⁺ channel subunits and auxiliary proteins, A- or M-type voltage-gated K⁺ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA_B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated currentI _h; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na⁺ channels underlying persistent Na⁺ currents or GABA_A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

Key Words: Epilepsy, channelopathy, antiepileptic drug, sodium channel, calcium channel, potassium channel, GABA receptor, glutamate receptor, GABA transporter, glutamate transporter, gap junction

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Molecular targets for antiepileptic drug development

Brian S Meldrum

Michael A Rogawski

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Molecular targets for antiepileptic drug development

Brian S Meldrum

Michael A Rogawski

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