Adverse Outcome Pathway on binding to the picrotoxin site of ionotropic GABA receptors leading to epileptic seizures in adult brain [electronic resource] /
Ping Gong and Edward J. Perkins
- Paris : OECD Publishing, 2019.
- 57 p.
- OECD Series on Adverse Outcome Pathways, no.11 2415170X ; .
- OECD Series on Adverse Outcome Pathways, no.11. .
This AOP begins with the interaction of chemicals to the picrotoxin binding site of the ionotropic GABA receptor complex causing blockage of the ion channel. As a result, decrease in inward chloride conductance occurs, followed by a reduction in postsynaptic inhibition, reflected as reduced frequency and amplitude of spontaneous inhibitory postsynaptic current or abolishment of GABA-induced firing action. Consequently, the resistance of excitatory neurons to fire is decreased, resulting in the generation of a large excitatory postsynaptic potential (EPSP) that causes voltage-gated Na+ to open, which results in action potentials. The depolarisation is followed by a period of hyper-polarisation mediated by Ca2+-dependent K+ channels or GABA-activated Cl− influx, which becomes smaller, gradually disappears, and is replaced by a depolarisation known as "paroxysmal depolarizing shift" (PDS). A PDS is an indication of epilepsy at the cellular level and initiates the adverse outcome at the organismal level of epileptic seizure.