GABA(A) receptor internalization during seizures.
A rapid modification in the postsynaptic gamma-aminobutyric acid (GABA(A)) receptor population occurs during the prolonged seizures of status epilepticus (SE). This rapid modification contributes to a reduction in GABA-mediated inhibition and the development of benzodiazepine pharmacoresistance. Previous hypotheses to explain the modification have included an alteration in the structural composition or posttranslational modification of the receptors. In a cultured hippocampal neuron model, we found that there was differential subcellular distribution of GABA(A) receptor subunits and that the constitutive internalization of GABA(A) receptors containing a beta2/3 subunit was rapid and activity-dependent. Based on this finding, we posit that an activity-dependent increase in the rate of internalization of synaptic GABA(A) receptors during SE contributes to the reduction in inhibitory transmission and the development of benzodiazepine pharmacoresistance.
Goodkin
Howard P
HP
Department of Neurology, University of Virginia, Health Sciences Center, Charlottesville, Virginia 22908, USA.
Sun
Chengsan
C
Yeh
Jwu-Lai
JL
Mangan
Patrick S
PS
Kapur
Jaideep
J
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance; D004594:Electrophysiology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D013226:Status Epilepticus / Q000188:drug therapy* / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D011963:Receptors, GABA-A; D001569:Benzodiazepines