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<!-- PLEASE DO NOT DELETE THIS TEMPLATE --> {{Sandbox_Reserved_Tims_CHEM412}} <!-- PLEASE ADD YOUR CONTENT BELOW HERE --> =Epileptic drugs at Voltage-Gated Sodium Ion Channel= ==Introduction== <Structure load='2kav' size='500' frame='true' align='right' caption='Structure of one subunit of the VGSC, from pdb model <nowiki>"2kav"</nowiki>' scene='vgsc_original/1' /> Under normal circumstances, the voltage gated sodium channel, or (<scene name='Sandbox_Reserved_695/Vgsc_original/1'>VGSC</scene>), serve to propagate the action potential down the axon, responding to elevated intracellular potential by opening the channel, allowing the rapid influx of sodium ions, which elevates the potential further, propagating the action potential. In a seizure, the synchronized activity of action potentials leads to very high frequency action potentials, leading to muscular convulsions and other symptoms <ref>McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol. 2001;63:815-46.</ref>. However, anticonvulsant drugs suppress seizures by limiting the high frequency firing of action potentials. These drugs do not interfere heavily with normal neurological activity, because they have little effect in neurons with normal resting potentials <ref>Rogawski, M., & Löscher, W. (2004). The neurobiology of antiepileptic drugs. Nature Reviews. Neuroscience, 5(7), 553-564.</ref> ==Structure== Structural determination of the VGSC has revealed it to be composed of four homologous domains, each of which has six transmembrane regions, while the pore is composed of the S5 and S6 segments <ref>Sato C, Ueno Y, Asai K, Takahashi K, Sato M, Engel A, Fujiyoshi Y: The voltage-sensitive sodium channel is a bell-shaped molecule with several cavities. Nature 2001, 409:1047-1051.</ref>. [[Image:VGSC_SCHEMATIC.png]](Image from Wikimedia<ref>http://en.wikipedia.org/wiki/File:Sodium-channel.svg</ref> For a better illustration of the structure, see [http://genomebiology.com/content/figures/gb-2003-4-3-207-1.jpg Schematic of Transmembrane regions of VGSC] <ref>F.H. Yu, W.A. Catterall Overview of the voltage-gated sodium channel superfamily Genome Biol., 4 (2003), pp. 207–214</ref>.) For better illustration of the structures at work, the structure shown will only contain one subunit. The <scene name='Sandbox_Reserved_695/Vgsc_alphabeta/2'>secondary structure</scene> includes alpha helices (blue) and beta strands (red). The <scene name='Sandbox_Reserved_695/Vgsc_hydrophobicpolar/2'>hydrophobicity</scene> of the structure reveals that the {{Template:ColorKey_Hydrophobic}} and {{Template:ColorKey_Polar}} residues are not exactly easy to illustrate in their membrane bound and subunit bound region., but the somewhat diffuse polar regions of the molecule are instrumental in providing the channel with enough hydrophillic residues to allow the passage of ions without allowing significant passage of solvent. In coordination with the hydrophobicity illustration, the <scene name='Sandbox_Reserved_695/Vgsc_evolutionaryconservation/2'>evolutionary conservation</scene> plot shows that both some of the hydrophobic and hydrophillic residues are highly conserved {{Template:ColorKey_ConSurf_NoYellow}}. ==Active Site and Interactions== The channel protein mostly interacts with sodium ions under normal circumstances, but the activity of the anti-epileptic drugs is obviously and important exception to be considered. The sodium ions are conveyed through the channel by favorable interactions with the <scene name='Sandbox_Reserved_695/Vgsc_anionic/1'>anionic residues </scene>, in particular, the <font color='red'>glutamic acid residues</font> that line the channel helix. Interestingly enough, several antiepileptic drugs that are known to work by altering VGSC activity have rather distinctive structures. Phenytoin, carbamazepine, and lamotrigine have rather different structures in three-dimensional space[http://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=2981395_zmo0101062060001.jpg](click the link for an excellent illustration). Carbamaepine is illustritive of the aromatic-amide domain that is common to these drugs. {{Wikipedia|Carbamazepine}} These drugs all act to inhibit the VGSC to prevent high frequency depolarizations consistent with seizures. Even more interesting, these three drugs all appear to bind at the same few residues in order to exert their inhibitory effect<ref>Kuo CC. (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol Pharmacol 54:712–721.</ref>. Bizarrely enough, this binding site also appears to overlap with the of some tricyclic antidepressants and anesthetics, although these drugs have drastically different effects from the anti-epileptic drugs.<ref>Yang, Y. C., Huang, C. S., & Kuo, C. C. (2010). Lidocaine, carbamazepine, and imipramine have partially overlapping binding sites and additive inhibitory effect on neuronal Na+ channels. Anesthesiology, 113(1), 160-174.</ref> The critical <scene name='Sandbox_Reserved_695/Vgsc_ligand_residues/2'>ligand binding residues</scene> for these drugs appear to be <font color='yellow'>Tyr-1771</font> and <font color='green'>Phe-1764</font>.<ref>Ragsdale DS, Avoli M. (1998) Sodium channels as molecular targets for antiepileptic drugs. Brain Res Rev 26:16–28</ref> Unfortunately, there does not appear to be adequate data for both residues to comment on the evolutionary conservation of these binding site residues. ==References== <references /> Original= <scene name='Sandbox_Reserved_695/Vgsc_orginal/2'>TextToBeDisplayed</scene> <scene name='Sandbox_Reserved_695/Vgsc_helix_sheet/1'>Alpha Helices and Beta Sheets</scene> <scene name='Sandbox_Reserved_695/Vgsc_ligand_residues/1'>Ligand Binding</scene> <scene name='Sandbox_Reserved_695/Vgsc_ligand_spacefill/1'>Ligand binding Space-fill</scene>

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