Subunit-specific trafficking of GABA(A) receptors during status epilepticus.
It is proposed that a reduced surface expression of GABA(A) receptors (GABARs) contributes to the pathogenesis of status epilepticus (SE), a condition characterized by prolonged seizures. This hypothesis was based on the finding that prolonged epileptiform bursting (repetitive bursts of prolonged depolarizations with superimposed action potentials) in cultures of dissociated hippocampal pyramidal neurons (dissociated cultures) results in the increased intracellular accumulation of GABARs. However, it is not known whether this rapid modification in the surface-expressed GABAR pool results from selective, subunit-dependent or nonselective, subunit-independent internalization of GABARs. In hippocampal slices obtained from animals undergoing prolonged SE (SE-treated slices), we found that the surface expression of the GABAR beta2/3 and gamma2 subunits was reduced, whereas that of the delta subunit was not. Complementary electrophysiological recordings from dentate granule cells in SE-treated slices demonstrated a reduction in GABAR-mediated synaptic inhibition, but not tonic inhibition. A reduction in the surface expression of the gamma2 subunit, but not the delta subunit was also observed in dissociated cultures and organotypic hippocampal slice cultures when incubated in an elevated KCl external medium or an elevated KCl external medium supplemented with NMDA, respectively. Additional studies demonstrated that the reduction in the surface expression of the gamma2 subunit was independent of direct ligand binding of the GABAR. These findings demonstrate that the regulation of surface-expressed GABAR pool during SE is subunit-specific and occurs independent of ligand binding. The differential modulation of the surface expression of GABARs during SE has potential implications for the treatment of this neurological emergency.
Goodkin
Howard P
HP
Department of Neurology, Health Sciences Center, University of Virginia, Charlottesville, Virginia 22908, USA.
Joshi
Suchitra
S
Mtchedlishvili
Zakaria
Z
Brar
Jasmit
J
Kapur
Jaideep
J
D000818:Animals; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013226:Status Epilepticus / Q000235:genetics / Q000378:metabolism*
D021122:Protein Subunits; D011963:Receptors, GABA-A