期刊
JOURNAL OF NEUROSCIENCE
卷 28, 期 2, 页码 376-384出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4346-07.2008
关键词
synaptic inhibition; protein kinase C; endocytosis; GABA(A) receptor; phosphorylation; status epilepticus
资金
- Medical Research Council [G120/972] Funding Source: Medline
- NIMH NIH HHS [MH071705, P20 MH071705] Funding Source: Medline
- NINDS NIH HHS [NS054770, R01 NS032403, R37 NS032403, R01 NS046478, NS 046478, NS 051195, NS 032403, R01 NS038572-10, R01 NS054770, R01 NS038572, P01 NS054900-02, R37 NS032403-15, NS 056359, NS 048045, P01NS054900, P01 NS054900, NS 038572] Funding Source: Medline
- MRC [G120/972] Funding Source: UKRI
- Medical Research Council [G120/972] Funding Source: researchfish
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 GABAARs on serine residues 408/9 (S408/9) in the beta 3 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 beta 3 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.
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