From the molecular point of view, different types of sodium channels can be distinguished regarding their main, α subunits, several of which have been cloned. One such a unit is thought to constitute a fully functional channel (5,6)(Fig. 1), which, however, can underlie modulation by other subunits (see later). In the rat, human, and mouse CNS, the α subunits are encoded by at least five different genes. Of these, SCN1A, SCN2A, and SCN3A (corresponding to rat sodium channels type I, II, III in older nomenclature) are closely related and give rise to sodium currents carried by channel proteins Nav1.1 through 1.3. Additionally, the SCN8A gene (Nav 1.6, formerly called NaCh6), and a tetrodotoxin (TTX)-insensitive SCN5A (Nav 1.5) have been described in the CNS, the latter of which is particularly interesting, as it is localized primarily in the limbic system, which has a relatively low seizure threshold. Furthermore, a glia-specific channel (SCN6A or NaG) is present in the CNS (7–13). Of these channels, Nav1.2 and Nav 1.6 sodium channels compose most of the channels in the neocortex and forebrain, whereas Nav 1.1 is expressed at much lower levels. At least in the rat, Nav 1.3 channels are expressed predominantly only during early ontogenetic stages (14,15); in the human brain, Nav 1.3 also is apparently encountered during adulthood in hippocampus, frontal lobe, and cerebellum (16). The channel α subunits are often associated with auxiliary β subunits in brain (β1, β2, and β3; Fig. 1), as well as in heart and skeletal muscle (β1 and β2) (17–19). These subunits, although not essential for channel function, can accelerate channel activation and inactivation (or decelerate it in the case of the β3 subunit, which is found mainly in juvenile tissue), shift steady-state inactivation in a negative direction, and (at least β2) appear to facilitate incorporation of channels into the membrane (5,6,17,20,21).
Figure 1. Putative structure of the α (encoded by SCN1A) and β (encoded by SCN1B) subunits of the voltage-gated sodium channel and mutations associated with generalized epilepsy with febrile seizures plus (GEFS+; solid circles) or severe myoclonic epilepsy of infancy (SMEI; grey squares). The channel consists of four consecutive domains (I–IV) with six transmembrane segments (1–6). Segment 4 acts as the voltage sensor (+). The domains associate to form a central pore. Mutations are shown as point mutations with exchange of amino acids at designated positions (e.g., T875M), insertions (ins), deletions (del), or splice site mutations (splice site). Electrophysiologic characterizations have been carried out on mutations T875M and R1648H, affecting the voltage sensors in domains II and IV, and C121W, affecting the β subunit, respectively (see text). The latter mutation prevents interaction with the α subunit. The only mutation so far found on another α subunit (encoded by SCN2A) consists of an exchange in R187W in domain I.
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Much like other voltage-gated channels, apart from molecular differences, sodium currents also fall into classes with different properties. Thus both activation and particularly the type of inactivation (fast vs. slow or noninactivating currents) can differ considerably. These functional differences are probably not related to the different molecular channel subtypes (see section on ion channels); nevertheless, their impact on neuronal excitability is qualitatively different. Most studies addressing sodium currents and epilepsy do not specifically focus on the functional current subtypes but discuss mainly fast inactivating currents. However, the noninactivating sodium current has been given increasing attention in recent years, so that it appears helpful to differentiate between fast and noninactivating functional states of the sodium current, at least for some aspects of this review.
Electrophysiologic properties of INa
The voltage-dependent fast inactivating sodium current (INa) is the principal current responsible for the depolarizing phase of the action potential and thus is the essential current for neuronal excitation in general. Consequently it can be considered to be indispensable also for the generation of epileptiform activity. Indeed, signal transmission in neuronal networks, and therefore synchronization among neurons as the characteristic process of epileptogenesis, are unthinkable without the existence of sodium currents. Computer models of neuronal networks generating epileptiform activity generally include INa(1,22–24). Further, albeit indirect, evidence for the crucial role of voltage-gated sodium channels for epileptogenesis can seen in the observation that several epileptogenic agents appear to exert their effect by enhancing sodium currents. Thus the convulsant drug pentylenetetrazol (PTZ) prolongs sodium-carried action potentials, and prolonged cocaine treatment, which induces seizures in animals, increases peak sodium current conductance (25,26), actions that might, however, also be attributed to interference with other channels. Unlike the noninactivating INa, the fast INa under normal circumstances is unlikely to affect excitability in general. Its properties (in comparison to INaP) are illustrated in Fig. 2. It shows fast, submillisecond activation, and usually fast inactivation with millisecond time constants will allow it only to code short signals as needed for information processing. After the signal, INa automatically falls silent. It substantially (∼80%) recovers only with a time constant of milliseconds. A further “safety factor” prevents INa from becoming fully available too fast: Prolonged inactivation of INa leading to recovery time constants of several seconds can be observed after short trains of, or even single, action potentials (27–29). Such prolonged inactivation (also termed “slow” by many authors) indeed regulates and limits backpropagation of action potentials in dendrites (30). As this phenomenon depends on frequency and duration of the previous depolarizations, this will particularly lead to a dampenening of INa with strong (epileptic) activity. One can speculate that loss of this slow inactivation would increase excitability and thus epileptogenicity, and future studies should investigate changes of slow inactivation with respect to epilepsy. Conversely, AEDs that strengthen or restore prolonged inactivation might be particularly helpful. Indeed, in one study on hamster striatal neurons, lamotrigine (LTG) appeared to prolong recovery from inactivation in this sense (31,32). A peculiar property of sodium currents—in a way opposing slow inactivation—is the resurgent current, which has been described only in cerebellar Purkinje neurons (Fig. 2). It consists of a pronounced inward current after moderate repolarization (e.g., to –30 mV) after strong depolarization (e.g., to 30 mV) (33). If such a current could be observed not only in the cerebellum (which lacks epileptogenicity) but also in seizure-prone areas such as the hippocampus (where it is not present, at least in nonepileptic tissue) (33), it could increase excitability and contribute to seizure generation. Again, future studies should clarify whether (in chronic epilepsy models) such sodium-channel behavior can be seen. Further, a conversion of otherwise fast-inactivation kinetics to slow ones would likewise support epileptogenesis. Several epileptogenic substances seem to act primarily by slowing the otherwise fast-inactivation kinetics of sodium channels and thereby increasing their open probability. Among these are the sodium-channel opener veratridine (34), the insecticides pyrethrin and DDT (35–38), and the venom of the scorpion Centruruides sculpturatus(39). An enhancement of INa, however, is probably not the main pathogenetic mechanism of epileptogenesis in general, because in some models (e.g., with strychnine and PTZ application in molluscan neurons), INa was found to be decreased (40,41).
Figure 2. Fast inactivating (INa), noninactivating (INaP), and resurgent (INa resurgent) sodium currents in Purkinje neurons of normal and mutant (null mutation of Nav1.6) mice. Currents were elicited by voltage steps, as given in diagram. Current–amplitude scaling is relative to peak amplitude of INa. Note that INa composes ∼98% of total current in normal mouse neurons, and that it decays to ∼10% of its peak amplitude within ∼5 ms. By contrast, 2% of the current does not inactivate, thus remaining as INaP. As a special feature of cerebellar Purkinje neurons, a sizeable current larger than the remaining INaP can be reelicited after repolarization and subsequent strong depolarization on stepping back to –30 mV. In a mutant mouse, where Nav1.6 is not functional, INa is normal, whereas INaP and particularly the resurgent current is reduced. Reprinted from ref. 33, with permission.
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Whereas INa is the current responsible for neuronal activity per se, there is compelling evidence that a persistent, noninactivating sodium current (INaP) is particularly instrumental in finely modulating neuronal excitability and thus possibly determining epileptogenicity, as it lacks the “safety factor” of automatic inactivation. The properties of INaP and its role in epileptogenesis are discussed in the following section.