Event:584

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Event Title

sodium channel, Inhibition

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Sodium channel inhibition leading to reduced survival MIE Moderate
sodium channel inhibition leading to increased predation MIE Strong
Sodium channel inhibition leading to congenital malformations MIE Strong
Sodium channel (Nav1.1) inhibition leading to population decline MIE

Chemical Initiators

The following are chemical initiators that operate directly through this Event:

  1. Carbamazepine
  2. Topiramate
  3. Tetrodotoxin
  4. Amiodarone
  5. Phenytoin
  6. Valproate
  7. Zonisamide
  8. Lidocaine

Taxonomic Applicability

Name Scientific Name Evidence Links

Level of Biological Organization

Biological Organization
Molecular

How this Key Event works

Voltage-gated sodium channels consist of an alpha subunit and auxiliary beta subunits. The alpha subunit is the ion pore-forming component of the channel and is organized into four homologous domains (I- IV), each with six trans-membrane alpha helices (S1-S6). Between the S5 and S6 segments, there is a pore loop which is a primary target for anti-epileptic drugs. The segments between S5 and S6 in each of the four domains create extracellular pore loops. Amino acid changes in the poor loops within domains II and IV determine if the ion channel is sensitive to sodium or calcium ions. Anti-epileptic, anti-arrhythmic and anesthetics all may bind this same site, but their action may be voltage-specific. For example, phenytoin is an ineffective block of hyperpolarized (e.g., -100mV) sodium channels, but is more effective at blocking progressively depolarized potentials (e.g., -80 to -30 mV).

How it is Measured or Detected

Voltage-clamp recordings of sodium currents is a general means of detection. ToxCast assay NVS_IC_rNaCh_site 2 also measures binding to the sodium channel receptor.

Evidence Supporting Taxonomic Applicability

References

Ragsdale, D.S. and Avoli, M. 1998. Sodium channels as molecular targets for antiepileptic drugs. Brain Research Reviews 26:16-28.

Pless, S.A., Galpin, J.D., Frankel, A., and Ahern, C.A. 2011. Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels. Nat Commun 2:351.