Voltage-activated sodium channel

The saxitoxins function by binding to a site on the extracellular surface of the voltage-activated sodium channel, interrupting the passive inward flux of sodium ions that would normally occur through the channel while it is in a conducting... 

Figure 2.2 Diagram of a voltage-activated sodium channel protein. The channel is composed of a long chain of amino acids intercormected by peptide bonds. The amino acids perform specific functions within the ion channel. The cylinders represent amino acid assemblies located within the membrane of the nerve cell and responsible for the foundation of the ion pore.

Therapeutic uses Cocaine has a local anesthetic action that represents the only current rationale for the therapeutic use of cocaine-, cocaine is applied topically as a local anesthetic during eye, ear, nose, and throat surgery. While the local anesthetic action of cocaine is due to a block of voltage-activated sodium channels, an interaction with potassium channels may contribute to cocaine s ability to cause cardiac arrhythmias. [Note Cocaine is the only local anesthetic that causes vasoconstriction. This effect is responsible for the necrosis and perforation of the nasal septum seen in association with chronic inhalation of cocaine powder.]... 

Marban, E., Yamagishi, T., and TomaselU, F. 1998. Structure and function of voltage-activated sodium channels. J. Physiol 508, 647-657. 

Figure 1. Diagram showing some ion channel targets for venom toxins a generalized insect synaptic junction. Sites 1-3 are presynaptic, 4 is postsynaptic. Site 1 is the insect voltage active sodium channel, targeted by scorpion toxins and spider toxins. Site 2 is the voltage-activated calcium channel. Block of Ms channel invents calcium entry and transmitter release. Site 3 is the latrotoxin receptor, which is involved in the exocytotic release mechanism. Site 4 is the transmitter activated cation channel, which is blocked by acylpolyamine spider toxins. (See Table I for list of toxins acting at these sites).

Brevetoxins Unique Activators of Voltage-Sensitive Sodium Channels... 

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

The epilepsies constitute a common, serious neurological disorder in humans, affecting approximately 60 million people worldwide. Well in excess of 40 distinct epileptic syndromes have been identified to date. Current treatment is only symptomatic except in uncommon instances when surgical treatment is possible. While available antiseizure medications target ion channels such as the y-amino-butyric acid (GABA)a receptor and voltage activated sodium (Na+) channels, current research seeks to elucidate the cellular and molecular mechanisms by which a normal brain becomes epileptic. Hopefully, this research will lead to the identification of new targets for which small molecules can be identified and used for prevention or cure of epilepsy. 

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

It blocks voltage-sensitive sodium channels, modulates the voltage-activated Ca currents, and increases potassium conductance. 

Poli MA, Mende TJ, Baden DG (1989) Brevetoxins, unique activators of voltage-sensitive sodium channels, bind to specific sites in rat brain synaptosomes. Mol Pharmacol 30 129-135 Pullaiah KC, Surapaneni RK, Rao CB, Albizati KF, Sullivan BW, Faulkner DJ, He CH, Clardy J (1985) Dictyoxetane, a novel diterpene from the brown alga Dictyota dichotoma from the Indian Ocean. J Org Chem 50 3665-3666... 

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. 

Carbamazepine exerts its anticonvulsant activity through its own action on voltage sensitive sodium channels and those of its relatively stable 10-11-epoxide. The compound shows a number of potential toxicities including skin rash, hepatic necrosis and teratogenicity. It is possible the 10-11-epoxide is the causative agent, but struc-... 

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