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Reduction, Ionotropic GABA receptor chloride channel conductance leads to Reduction, Neuronal synaptic inhibition
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain||adjacent||High||High||Ping Gong (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
A decline in conductance through chloride channels in iGABARs causes a reduction in GABA-mediated inhibition of neuronal synaptic signaling, which is reflected as decreased frequency and amplitude of iGABAR-mediated spontaneous inhibitory postsynaptic currents or abolishment of GABA-induced firing action (Newland and Cull-Candy 1992). For instance, whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency and amplitude of GABAA receptor mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and the amplitude of GABA-evoked postsynaptic currents, whereas in extracellular field recordings from the BLA, RDX induced prolonged, seizure-like neuronal discharges (Williams et al. 2011). These pieces of cellular level evidence support that binding to the GABAA receptor convulsant site is the primary mechanism of seizure induction by RDX and that the key event of reduction of GABAergic inhibitory transmission in the amygdala is involved in the generation of RDX-induced seizures.
Evidence Supporting this KER
Chloride channels play an important role in regulating neuronal excitability, especially in the context of fast synaptic inhibition mediated by GABAA receptors. But in order for chloride channels to reduce excitability, chloride driving force must be maintained to keep a dynamic balancing of chloride influx and efflux, which also involves a variety of other ion species (Prescott 2014). If chloride regulation is compromised, the efficacy of fast synaptic inhibition can be compromised with adverse effects such as reduced neuronal inhibition.
Uncertainties and Inconsistencies
As a heteropentameric receptor, the iGABAR consists of five protein subunits arranged around a central pore to form an ion channel through the membrane. The subunits are drawn from a pool of 19 distinct gene products, including six alpha, three beta, and three gamma subunits. The high diversity of subunit genes, in combination with alternative splicing and editing, leads to an enormous variety and, consequently, variability in function and sensitivity. This constitutes the main source of uncertainties.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
iGABARs and synaptic neurons are present in animals throughout the animal kingdom, therefore this event is applicable to a wide range of species from earthworm to humans. This relationship has been shown directly in rats (Williams et al. 2011) and guinea pig (Juarez et al. 2013).
Juarez E H, Ochoa-Cortes F, Miranda-Morales M, Espinosa-Luna R, Montano L M, Barajas-Lopez C. Selectivity of antagonists for the Cys-loop native receptors for ACh, 5-HT and GABA in guinea-pig myenteric neurons. Auton Autacoid Pharmacol 2013; 34(1-2):1-8.
Macdonald R L, Olsen R W. GABAA receptor channels. Annu. Rev. Neurosci. 1994;17:569–602.
Newland C F, Cull-Candy S G. On the mechanism of action of picrotoxin on GABA receptor channels in dissociated sympathetic neurones of the rat. J Physiol 1992; 447: 191–213.
Olsen R W, DeLorey T M. Chapter 16. GABA and Glycine: GABA Receptor Physiology and Pharmacology. In: Siegel GJ, Agranoff BW, Albers RW, et al. (Eds), Basic Neurochemistry: Molecular, Cellular and Medical Aspects (6th edition), Philadelphia: Lippincott-Raven; 1999.
Prescott S A. Chloride channels. In: Jaeger D and Jung R (Eds.), Encyclopedia of Computational Neuroscience, Springer, New York, 2014. pp.1-4.
Williams L R, Aroniadou-Anderjaska V, Qashu F, Finne H, Pidoplichko V, Bannon D I et al. RDX binds to the GABA(A) receptor-convulsant site and blocks GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced seizures. Environ Health Perspect 2011; 119(3):357-363.