Deficits in Phosphorylation of GABA(A) Receptors by Intimately Associated Protein Kinase C Activity Underlie Compromised Synaptic Inhibition During Status Epilepticus

Overview

Journal J Neurosci

Specialty Neurology

Date 2008 Jan 11

PMID 18184780

Citations 84

Authors

Miho Terunuma

Jianwei Xu

Mansi Vithlani

Werner Sieghart

Josef Kittler

Menelas Pangalos

Philip G Haydon

Douglas A Coulter

Stephen J Moss

Affiliations

Soon will be listed here.

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 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.

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