Deficits in phosphorylation of GABA(A) receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus.
Status epilepticus (SE) is a progressive and often lethal human disorder characterized by continuous or rapidly repeating seizures. Of major significance in the pathology of SE are deficits in the functional expression of GABA(A) receptors (GABA(A)Rs), the major sites of fast synaptic inhibition in the brain. We demonstrate that SE selectively decreases the phosphorylation of GABA(A)Rs on serine residues 408/9 (S408/9) in the beta3 subunit by intimately associated protein kinase C isoforms. Dephosphorylation of S408/9 unmasks a basic patch-binding motif for the clathrin adaptor AP2, enhancing the endocytosis of selected GABA(A)R subtypes from the plasma membrane during SE. In agreement with this, enhancing S408/9 phosphorylation or selectively blocking the binding of the beta3 subunit to AP2 increased GABA(A)R cell surface expression levels and restored the efficacy of synaptic inhibition in SE. Thus, enhancing phosphorylation of GABA(A)Rs or selectively blocking their interaction with AP2 may provide novel therapeutic strategies to ameliorate SE.
Terunuma
Miho
M
Department of Neuroscience, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Xu
Jianwei
J
Vithlani
Mansi
M
Sieghart
Werner
W
Kittler
Josef
J
Pangalos
Menelas
M
Haydon
Philip G
PG
Coulter
Douglas A
DA
Moss
Stephen J
SJ
D000818:Animals; D019921:Biotinylation / Q000379:methods; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000473:pathology; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010862:Pilocarpine; D011493:Protein Kinase C / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D021122:Protein Subunits; D011963:Receptors, GABA-A; D010862:Pilocarpine; D015240:Phorbol 12,13-Dibutyrate; D012694:Serine; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases