The majority of AEDs introduced since 1938 have properties that suggest they act on voltage-dependent sodium channels (Table 2). As suggested above, this emphasis on Na⁺ channel inactivation may be a consequence of the screening procedures employed.

Advances in the molecular biology of voltage-dependent Na⁺ channels now permit a precise definition of potential target sites for anticonvulsant drug action.^24,55

The principal element of a voltage-dependent Na⁺ channel is the α subunit (260 kDa), which has four domains, each with six transmembrane helices, four of which form the voltage sensor and two (S5 and S6 connected by the P-loop that confers the ion-selectivity) forming the “pore domain.” The α subunit is assembled with subsidiary β1 to β4 subunits. Different cells express different α subunits; in the brain, I, II, IIA, and NaCh6 α subunits are found. Following an action potential, there is a transient process of inactivation during which the Na⁺ channel is unresponsive to voltage. This inactivation has fast and slow components that have been shown by site-directed mutagenesis to have distinct structural correlates. The loop linking domains III and IV act as a mechanical gate—“hinged lid”—producing fast inactivation. It can be rendered inoperative by proteolysis or site-directed mutagenesis.

Site-directed mutagenesis was also used to establish that three amino acids in the sixth transmembrane segment in domain 4 play a critical role in the binding of local anesthetics, phenytoin, and carbamazepine.^12,82 Recently it has been shown that binding of lamotrigine and some related compounds is dependent on the same three amino acid residues in IV6 and also two in III6.^12,82,119

Thus, there are specific sites within the α subunit that provide targets for AEDs, prolonging inactivation of voltage-sensitive Na⁺ channels. The four different α subunits expressed in the brain also may be seen as distinct targets.

There is a further function of Na⁺ channels that is a target for AEDs. They provide persistent, noninactivating Na⁺ currents that contribute to certain patterns of burst firing.¹⁰³ Phenytoin diminishes these currents,¹⁵ as do topiramate and valproate.

Thus, Na⁺ channels provide a multiplicity of targets. Acting on two families of sodium channels may be advantageous for anticonvulsant efficacy. There are homologies of sequence and morphology between voltage-sensitive Na⁺, Ca²⁺, and K⁺channels, and some known Ca²⁺ channel blockers also act on Na⁺ channels (e.g., flunarizine). Thus, designing compounds that block both classes of ion channel may lead to improved AED efficacy.

These Ca²⁺ channels were originally classified in terms of biophysical measurements across neuronal membranes, determining voltage activation threshold, conductance per channel, and inactivation kinetics, giving T-, N-, and L-type Ca²⁺ channels. Other channels (P/Q, N, and R) were later identified (Table 3).^13,105 The role of voltage-gated calcium channels in immunoglobin (IG) E has recently been reviewed.^43,50

As explained in Chapter 136, there is an apparent link between action against 2- to 3-Hz absence attacks and a partial suppression of Ca²⁺ T-channel conductance.²² The T-type calcium current makes a specific contribution to oscillatory responses in thalamic neurons, and these oscillations play a critical role in 2- to 3-Hz discharges in the cortex and thalamus.¹²² Thus, the suppression of absence attacks by ethosuximide and dimethadione has been attributed to the reduction in T Ca²⁺ currents they produce, although a variety of other effects on ion channels may also be involved. High concentrations of valproate reduce T currents in primary afferent neurons.⁴⁶ Zonisamide also reduces T Ca²⁺ currents. Perhaps T-type Ca²⁺ channels are best regarded as an auxiliary or supplementary target to broaden the spectrum of activity of a compound intended to affect more than one molecular mechanism.

The greatest interest in terms of targets for novel drugs are the high-voltage-activated channels designated as P/Q, N, and R type (Cav 2.1 to 2.3), because of their presynaptic role controlling release of neurotransmitters. N-type channels appear to be important for synaptic release of monoamines and some peptides.¹⁰⁹ The P/Q-type Ca²⁺ channels are important for the release of monoamines, glutamate, and GABA.³⁷ There is evidence suggesting that some established and novel AEDs act on presynaptic Ca²⁺ channels.^30,53,98,111 Thus, P/Q-, N-, and R-type calcium channels appear to be key targets for the development of novel AEDs. It should be remembered, however, that mutations leading to impaired function of P/Q-type channels produce ataxia and absence seizures in man and mouse.

Potassium selective ion channels were originally differentiated in biophysical studies and are found in all mammalian cells. Today they are classified partially on the basis of their functional properties and partially on the basis of their evolutionary origin and molecular morphology^120,121 (see Tables 1 and 4). The 75 or more distinct α subunits identified in genetic studies provide four main families: Voltage gated (Kv1 to Kv10); calcium activated (Kca2.1 to 2.3, Kca1.1); inwardly rectifying (kir); and the two-pore K⁺ channels that provide the “leak” currents (K_2P). The voltage-gated and calcium-activated K⁺ channels are part of the S4 superfamily and have an α subunit with a core formed by six putative transmembrane helices. The S1 to S4 segment provides the voltage sensor domain homologous with that of the Na⁺ and Ca⁺⁺ion channels. A linker helix connects this to the S5 and S6 segments, which, with their P-loop, form the ion-selective channel.^21,56,57 Opening K⁺ channels has the effect of hyperpolarizing neurons or reversing depolarizing actions. At least two different calcium-activated K⁺ channels underlie afterhyperpolarizations.⁸⁹ One, SK_Ca, with a fast time course, is mediated by small conductance channels; the other has a slow time course and is modulated by numerous G-protein–coupled neurotransmitters. Studies of dentate granule cells isolated from patients with temporal lobe epilepsy show a prominent delayed rectifier outward current (I_K) whose steady-state voltage dependence differs according to whether the specimen shows Ammon horn sclerosis or not.³

Many compounds that act as potassium channel blockers are convulsant, for example, 4-aminopyridine and various scorpion and sea anemone toxins such as dendrotoxin I and pandinus toxin.^44,108 In in vitro systems, 4-aminopyridine–induced discharges are commonly used as a model for analyzing seizure activity. Several drugs thought to act as potassium channel openers such as chromakalim, minoxidil, diazoxide, and pinacidil show antiepileptic effects when injected intracerebroventricularly in rodent models of epilepsy.^32,80 The most definitive data concern a drug retigabine, developed as a GABA modulator but shown in 2000 to activate Kv7.2 and Kv7.3 channels responsible for the M-type current on soma and dendrites and the slow K⁺ current (I_ks) on axons.^88,115 Mutations involving the genes encoding these channels (KCNQ2/KCNQ3) are responsible for benign familial neonatal convulsions.^19,96 Retigabine shifts the voltage dependence of the M current to hyperpolarized potentials, speeds the rate of activation, and slows inactivation. It has a similar effect on Kv7.4 and Kv7.5, which are also expressed in the brain, but is inactive on Kv7.1, the cardiac homolog. Experiments with chimeric channels and point mutations^90,118 have shown that the pore domain is the site of action of retigabine and that its action is dependent on a tryptophan residue on S5 found in KCNQ2 to 5 but not in KCNQ1. Further compounds have been identified with a similar channel-opening effect and activity in rodent models of epilepsy.¹¹⁷ Thus, the potassium channels responsible for the M current are clearly identified as a target for AEDs. Genetic and pharmacologic data suggest that the voltage-gated K channels responsible for the A-type K⁺ currents, which play an important role in controlling the excitatory threshold in synaptic terminals, are also an important potential target for novel AEDs,^21,69 but drugs potentiating these currents have yet to be identified. The calcium-activated channels and the inwardly rectifying and leak currents may also be targets, but evidence is less clear.

Many reports describe effects of established AEDs (such as phenytoin, carbamazepine, lamotrigine, and levetiracetam) on various K⁺ currents,⁶⁹ but the significance of these for antiepileptic effect remains uncertain.