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- Title
Deficits in Phosphorylation of GABA<sub>A</sub> Receptors by Intimately Associated Protein Kinase C Activity Underlie Compromised Synaptic Inhibition during Status Epilepticus.
- Authors
Terunuma, Miho; Jianwei Xu; Vithlani, Mansi; Sieghart, Werner; Kittler, Josef; Pangalos, Menelas; Haydon, Philip G.; Coulter, Douglas A.; Moss, Stephen J.
- Abstract
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 GABAA receptors (GABAARs), the major sites of fast synaptic inhibition in the brain. We demonstrate that SE selectively decreases the phosphorylation of GABAARs on serine residues 408/9 (S408/9) in the β3 subunit by intimately associated protein kinase C isoforms. Dephosphorylation of S408/9 unmasks a basic patchbinding motif for the clathrin adaptor AP2, enhancing the endocytosis of selected GABAAR subtypes from the plasma membrane during SE. In agreement with this, enhancing S408/9 phosphorylation or selectively blocking the binding of the β3 subunit to AP2 increased GABAAR cell surface expression levels and restored the efficacy of synaptic inhibition in SE. Thus, enhancing phosphorylation of GABAARs or selectively blocking their interaction with AP2 may provide novel therapeutic strategies to ameliorate SE.
- Subjects
PHOSPHORYLATION; GABA receptors; PROTEIN kinase C; BRAIN diseases; ENDOCYTOSIS
- Publication
Journal of Neuroscience, 2008, Vol 28, Issue 2, p376
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4346-07.2008