Voltage-gated sodium channel modulators

Tan J, Soderlund DM (2011) Independent and joint modulation of rat Nav1.6 voltage-gated sodium channels by coexpression with the auxiliary betal and beta2 subunits. Biochem Biophys Res Commun 407 788-792... 

Voltage-gated sodium channels generate the rapid regenerative upstroke of action potentials and hence play a central role in modulation of the firing activity of excitable cells. They form heterotrimeric transmembrane Na+-conducting pores... 

A variety of toxins that modulate voltage-gated sodium channels have been used to probe channel function. They can be classified on the basis of five discrete binding sites (Table 1). These binding sites are commonly found on all a-subunits and are being characterized at the molecular level. The sensitivity to the puffer fish poison tetrodotoxin (TTX) has been used to subdivide voltage-gated sodium channels (Table 3). 

Malhotra JD, Meadows L, Ragsdale DS, Hortsch M, Isom LL 1999 Cytoplasmic domains of voltage-gated sodium channel P subunits are essential for ankyrin recruitment and channel modulation in heterologous expression systems. Soc Neurosci Abstr 25 1731... 

Voltage-gated Sodium Channel (vgSCh) Modulators... 

Hedrich R, Marten I (2011) TPCl-SV channels gain shape. Mol Plant 4 428 41 Huang CJ, Moczydlowski E (2001) Cytoplasmic polyamines as permeant blockers and modulators of the voltage-gated sodium channel. Biophys J 80 1262-1279 Hughes G, Khan YM, East M, Lee AG (1995) Effects of polycations on Ca binding to the Ca -ATPase. Biochem J 308 493—499... 

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

Richardson, P. J., Mizuguchi, K., Jackson, A. P. Beta3 an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channels gating with distinct kinetics, Proc. Natl. Acad. Sci. USA 2000, 97, 2308-2313. 

Undrovinas AI, Shander GS, Makielski JC 1995 Cytoskeleton modulates gating of voltage-dependent sodium channel in heart. Am J Physiol 269 H203-H214... 

Modulation of ion channels in the brain is the mechanism of action of several antiepileptic drugs. Even though the structures of voltage-gated sodium, calcium, and potassium channels in the brain and in the heart are different, it is not inconceivable that in some circumstances some antiepileptic drugs may lose their specificity and alter cardiac excitability. 

Qu Y, Rogers JC, Chen SF, McCormick KA, Scheuer T, CatteraU WA 1999 Functional roles of the extracellular segments of the sodium channel alpha subunit in voltage-dependent gating and modulation by beta 1 subunits. J Biol Chem 274 32647-32654... 

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