Sandbox Reserved 695

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This Sandbox is Reserved from 30/01/2013, through 30/12/2013 for use in the course "Biochemistry II" taught by Hannah Tims at the Messiah College. This reservation includes Sandbox Reserved 686 through Sandbox Reserved 700.
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Epileptic drugs at Voltage-Gated Sodium Ion ChannelEpileptic drugs at Voltage-Gated Sodium Ion Channel

IntroductionIntroduction

<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 (), 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 [1]. 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 [2]

StructureStructure

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 [3]. (Image from Wikimedia[4] For a better illustration of the structure, see Schematic of Transmembrane regions of VGSC [5].)

For better illustration of the structures at work, the structure shown will only contain one subunit. The includes alpha helices and beta strands. The of the structure reveals that the Hydrophobic and 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 plot shows that both some of the hydrophobic and hydrophillic residues are highly conserved .

Active Site and InteractionsActive 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 , in particular, the glutamic acid residues 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[1](click the link for an excellent illustration). Carbamaepine is illustritive of the aromatic-amide domain that is common to these drugs. Carbamazepine in Wikipedia


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[6]. 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.[7]

The critical for these drugs appear to be Tyr-1771 and Phe-1764.[8] Unfortunately, there does not appear to be adequate data for both residues to comment on the evolutionary conservation of these binding site residues.

ReferencesReferences

  1. ↑ McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol. 2001;63:815-46.
  2. ↑ Rogawski, M., & Löscher, W. (2004). The neurobiology of antiepileptic drugs. Nature Reviews. Neuroscience, 5(7), 553-564.
  3. ↑ 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.
  4. ↑ http://en.wikipedia.org/wiki/File:Sodium-channel.svg
  5. ↑ F.H. Yu, W.A. Catterall Overview of the voltage-gated sodium channel superfamily Genome Biol., 4 (2003), pp. 207–214
  6. ↑ Kuo CC. (1998) A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol Pharmacol 54:712–721.
  7. ↑ 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.
  8. ↑ Ragsdale DS, Avoli M. (1998) Sodium channels as molecular targets for antiepileptic drugs. Brain Res Rev 26:16–28

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