API

Event: 64

Key Event Title

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Reduction, Ionotropic GABA receptor chloride channel conductance

Short name

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Reduction, Ionotropic GABA receptor chloride channel conductance

Biological Context

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Level of Biological Organization
Cellular

Cell term

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Cell term
neuron


Organ term

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Organ term
brain


Key Event Components

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Process Object Action
GABA-gated chloride ion channel activity chloride decreased

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Blocking iGABA receptor ion channel leading to seizures KeyEvent

Stressors

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Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rats Rattus norvegicus High NCBI
mouse Mus musculus High NCBI
Drosophila melanogaster Drosophila melanogaster High NCBI

Life Stages

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Sex Applicability

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Key Event Description

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This key event occurs at the cellular level and is characterized by a dose-dependent post-synaptic inhibition of membrane currents in iGABAR-containing cells, especially neuronal cells (Dichter and Ayala 1987; Bromfield et al. 2006), leading to the reduction of iGABAR chloride channel conductance.


How It Is Measured or Detected

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The change in membrane conductance can be measured by determining the alteration (i.e., inhibition) in muscimol-stimulated (Banerjee et al. 1999) or GABA-induced uptake (Babot et al. 2007) of 36Cl- in cortical and cerebellar membranes or primary cerebellar granule cell cultures, prior to and after exposure to a GABA antagonist. Inglefield and Schwartz-Bloom (1998) reported a Cl--sensitive fluorescent dye-based method where to measure real-time changes in intracellular chloride concentration with UV laser scanning confocal microscopy.


Domain of Applicability

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Banerjee et al. (1999) reported functional modulation of GABAA receptors by Zn2+, pentobarbital, neuroactive steroid alphaxalone, and flunitrazepam in the cerebral cortex and cerebellum of rats undergoing status epilepticus induced by pilocarpine.

Babot et al. (2007) measured the reduction in mouse GABAA receptor function by 3 μM dieldrin using the GABA-induced 36Cl- uptake method.

Bromfield et al. (2006) reviewed evidence for GABAA receptors in human and mammalian brains, whereas Narahashi (1996) and Costa (2015) reviewed organochlorine and some pyrethroid compounds as insecticides with the target site of chloride channel.

Grolleau and Sattelle (2000) reported a complete blocking of inward current by 100 μM picrotoxin in the wild-type RDL (iGABAR) of Drosophila melanogaster.


References

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Babot Z, Vilaro MT, Sunol C. (2007) Long-term exposure to dieldrin reduces gamma-aminobutyric acid type A and N-methyl-D-aspartate receptor function in primary cultures of mouse cerebellar granule cells. J. Neurosci. Res. 85(16), 3687-3695.

Banerjee PK, Olsen RW, Snead OC, III. (1999) Zinc inhibition of gamma-aminobutyric acid(A) receptor function is decreased in the cerebral cortex during pilocarpine-induced status epilepticus. J Pharmacol Exp Ther 1999; 291(1):361-366.

Bromfield EB, Cavazos JE, Sirven JI. (2006) Chapter 1, Basic Mechanisms Underlying Seizures and Epilepsy. In: An Introduction to Epilepsy [Internet]. West Hartford (CT): American Epilepsy Society; Available from: http://www.ncbi.nlm.nih.gov/books/NBK2510

Costa LG. (2015) The neurotoxicity of organochlorine and pyrethroid pesticides. Handb Clin Neurol. 131:135-48.

Dichter MA, Ayala GF. (1987) Cellular mechanisms of epilepsy: a status report. Science 237(4811), 157-164.

Gong P. Hong HH, Perkins EJ. (2015) Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers. Biomark. Med. 9(11):1225-39.

Grolleau F, Sattelle DB. (2000) Single channel analysis of the blocking actions of BIDN and fipronil on a Drosophila melanogaster GABA receptor (RDL) stably expressed in a Drosophila cell line. Br J Pharmacol. 130(8):1833-42.

Inglefield JR, Schwartz-Bloom RD. (1998) Optical imaging of hippocampal neurons with a chloride-sensitive dye: early effects of in vitro ischemia. J Neurochem. 70(6):2500-9.

Narahashi T. (1996). Neuronal ion channels as the target sites of insecticides. Pharmacol Toxicol. 79(1):1-14.