Key Event Title
Key Event Component
|GABA-gated chloride ion channel activity||chloride||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures||KeyEvent|
Level of Biological Organization
|Drosophila melanogaster||Drosophila melanogaster||Strong||NCBI|
How This Key Event Works
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
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.
Evidence Supporting Taxonomic Applicability
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 GABA-A receptors in human and mammalian brains.
Grolleau and Sattelle (2000) reported a complete blocking of inward current by 100 μM picrotoxin in the wild-type RDL (iGABAR) of Drosophila melanogaster.
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
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.