Key Event Title
Key Event Component
|sodium channel inhibitor activity||sodium channel protein type 1 subunit alpha||decreased|
|signaling||sodium channel protein type 1 subunit alpha||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Sodium channel inhibition leading to reduced survival||MolecularInitiatingEvent|
|sodium channel inhibition leading to increased predation||MolecularInitiatingEvent|
|Sodium channel inhibition leading to congenital malformations||MolecularInitiatingEvent|
|Sodium channel (Nav1.1) inhibition leading to population decline||MolecularInitiatingEvent|
Level of Biological Organization
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
Evidence for Perturbation by Stressor
Overview for Molecular Initiating Event
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.