Sodium channels, voltage-dependent

Voltage-dependent sodium channels are a family of membrane proteins that mediate rapid Na+ influx, in response to membrane depolarization to generate action potentials in excitable cells. 

Molecularly, mammalian voltage-dependent sodium channels are composed of the main pore forming a subunit and smaller auxiliary (3 subunits. The rat brain sodium channel contains the 260-kD a subunit, the 36-kD (31 subunit and the 33-kD (32 subunit. The subunit stoichiometry is a (31 (32 = 1 1 1. 

Lamotrigine blocks voltage-dependent sodium channels and inhibits high-voltage activated Ca channels. 

Phenytoin inhibits voltage-dependent sodium channels. 

Topiramate affects voltage-dependent sodium channels, GABA receptors, high voltage Ca channels, and kainate a-amino-3-hydroxy-5-methylisox-azole-4-propionic acid subunits. 

Lombet A, Mourre C, Lazdunski M (1988) Interaction of insecticides of the pyrethroid family with specific binding sites on the voltage-dependent sodium channel from mammalian brain. Brain Res 459 44—53... 

Biochemical site of action Site 1 on voltage-dependent sodium channel Site 5 on voltage-dependent sodium channel Catalytic subunit of phosphorylase phosphatases Kainate receptor in central nervous system Unknown Ciguatoxin site 5 on voltage-dependent sodium channel Maitotoxin calcium channels... 

Ion channels are large proteins which form pores through the neuronal membrane. The precise structure and function of the ion channels depend on their physiological function and distribution along the dendrites and cell body. These include specialized neurotransmitter-sensitive receptor channels. In addition, some ion channels are activated by specific metal ions such as sodium or calcium. The structure of the voltage-dependent sodium channel has been shown to consist of a complex protein with both a hydrophilic and a hydrophobic domain, the former domain occurring within the neuronal membrane while the latter domain occurs both inside and outside the neuronal membrane. 

Four main mechanisms of action underlie the beneficial pharmaceutical effect of AED (1) blockade of the voltage-dependent sodium channels (2) increased GABAergic inhibition of neurotransmission (3) blockade of glutaminergic transmission (4) blockade of type T calcium channels. AEDs are thus classed according to their known predominant effect ... 

Lamotrigine has a broad spectrum of action and is effective in generalized and partial epilepsies. Its primary mechanism of action appears to be blockage of voltage-dependent sodium channels, although its effectiveness against absence seizures indicates that additional mechanisms may be active. Lamotrigine is almost completely... 

As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This compound has broad anticonvulsant activity, both in experimental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at therapeutically relevant concentrations. In several experimental studies, valproate caused an increase in brain GABA the mechanism was unclear. There is evidence that valproate... 

The primary action of the benzodiazepines as anticonvulsants is to enhance inhibition through their interaction with the GABAa receptor at the benzodiazepine binding site. However, there appears to be an additional action of benzodiazepines blocking voltage-dependent sodium channels. This effect is not seen at usual doses but is likely a factor in their use in the treatment of status epilepticus (discussed later). 

While its mechanism of action has not been clearly established, felbamate shows some activity as an inhibitor of voltage-dependent sodium channels in a manner similar to that of phenytoin and carbamazepine. Felbamate also interacts at the strychnine-insensitive glycine recognition site on the NMDA receptor-ionophore complex. Whether this effect is important to its anticonvulsant activity is not clear. 

Lamotrigine is an anticonvulsant medication that decreases sustained high-frequency repetitive firing of the voltage-dependent sodium channel, which may then decrease glutamate release (Leach... 

Carter, R. B., Vanover, K. E., Wilent, W., Xu, Z., Woodward, R. M., Illyin, V. I. Anti-allodynic and anti-hyperalgesic effects of the novel voltage-dependent sodium channel blocker Co102862 in a rat model of peripheral neuropathy, Adv. Ion Channel Res., San Francisco 1999, Abstract book, P-... 

Fitzgerald, E. M., Okuse, K., Wood, J. N., Dolphin, A. C., Moss, S. J. cAMP-dependent phosphorylation of the tetrodotoxin-resistant voltage-dependent sodium channel SNS, J. Physiol. 1999, 516, 433-446. 

Weiser, T., Brenner, M., Palluk, R., Bechtel, W.D., Ceci, A., Brambilla, A., Ensinger, H.A., Sagrada, A., Wienrich, M. BIIR 561 CL A novel combined antagonist of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties, J. Pharmacol. Exp. Ther. 1999, 289, 1343-1349. 

Topiramate blocks repetitive firing of cultured spinal cord neurons, as do phenytoin and carbamazepine. Its mechanism of action, therefore, is likely to involve blocking of voltage-dependent sodium channels. Topiramate also appears to potentiate the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites. Topiramate also depresses the excitatory action of kainate on AMPA receptors. It is possible that all three of these actions contribute to topiramate s anticonvulsant effect. 

Kava has also been shown to have mild anticonvulsant properties in animals, possibly involving voltage-dependent sodium channels. 

Batrachotoxin at present remains an important, indeed often essential, tool for mechanistic studies of the function of voltage-dependent sodium channels and for the investigation of the role of depolarization and/or influx of sodium ions on physiological functions. Batrachotoxin has been particularly useful in the study of the function of sodium channels, purified and reconstituted into artificial lipid bilayers. A summary and overview of the extensive studies with batrachotoxin appeared in 1986 (5). Since that time more than 100 articles dealing with the activity of batrachotoxin and/ or the radioligand batrachotoxinin A 20a-[ H]benzoate have appeared, and it is beyond the scope of the present review to summarize this extensive recent literature. A few selected developments are as follows allosteric enhancement of the action of batrachotoxins by pyrethroid insecticides... 

The second class of channels are the voltage-dependent sodium channels, where histrionicotoxins reduce conductances in a manner reminiscent of local anesthetics (61). The third class are the voltage-dependent potassium channels, where histrionicotoxins reduce conductances in a time- and stimulus-dependent manner. Structure-activity relationships for histrionicotoxins differ at the three classes of channels (61). 

Further studies have revealed that pumiliotoxin B interacts with voltage-dependent sodium channels to elicit an increased influx of sodium ions (101,102) and, in brain and heart preparations, a stimulation of phosphoino-sitide breakdown (101,103-106). The phosphoinositide breakdown can, via inositol trisphosphate, cause release of calcium from internal storage sites. The cardiotonic activity of pumiliotoxin B and various congeners and synthetic analogs correlates well with the stimulation of phosphoinositide breakdown (104,105). A number of studies on stimulation of sodium uptake by pumiliotoxin B and inhibition by local anesthetics and other agents have appeared (106-108). The effects of pumiliotoxin B on neuromuscular preparations have been reinterpreted as due primarily to effects on sodium channels, although additional direct effects on calcium mobilization remain possible (109). It has recently been proposed that pumiliotoxin B enhances the rate of activation of sodium channels (110). One characteristic effect of pumiliotoxin B is to elicit repetitive firing in neurons, apparently because of effects on sodium channel function (109-111). 

In summary, pumiliotoxin B and congeners now appear to represent another class of alkaloids that modulate the function of voltage-dependent sodium channels. They are valuable research tools, and perhaps models, for the development of new myotonic or cardiotonic agents. Direct effects of pumiliotoxin-A class alkaloids on calcium translocation, as originally proposed (99), still remain a possibility for further pharmacological study. 

Chiriquitoxin is nearly as toxic as tetrodotoxin, having an LD50 in mice of about 0.3 fig. Pharmacologically, chiriquitoxin, like tetrodotoxin, blocks voltage-dependent sodium channels, but in addition it apparently also blocks potassium channels (211,213). The effects of chiriquitoxin on potassium currents were prevented by tetrodotoxin. 

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