Brian S. Meldrum and Michael A. Rogawski2007
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 subunits of voltagegated
Na channels and also T-type voltage-gated Ca2 channels)
or influence GABA-mediated inhibition. Recently, 2–
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 GABAA 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 GABAB and metabotropic glutamate
receptors; hyperpolarization-activated cyclic nucleotide-
gated cation (HCN) channel subunits, responsible for hyperpolarization-
activated current Ih; 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
GABAA 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.
稿件提供人：张玉梅
