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The Journal of Neuroscience, January 9, 2008, 28(2):376-384; doi:10.1523/JNEUROSCI.4346-07.2008

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Cellular/Molecular
Deficits in Phosphorylation of GABA_A Receptors by Intimately Associated Protein Kinase C Activity Underlie Compromised Synaptic Inhibition during Status Epilepticus

Miho Terunuma,¹ Jianwei Xu,² Mansi Vithlani,^1,3 Werner Sieghart,⁵ Josef Kittler,⁴ Menelas Pangalos,⁶ Philip G. Haydon,¹ Douglas A. Coulter,² and Stephen J. Moss^1,3

¹Department of Neuroscience, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, ²Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, Departments of ³Pharmacology and ⁴Physiology, University College London, London WC1E 6BT, United Kingdom, ⁵Spitalgasse 4, Vienna A-1090, Austria, and ⁶Wyeth Research, Neuroscience Discovery, Princeton, New Jersey 08852

Correspondence should be addressed to Stephen J. Moss at the above address. Email: sjmoss{at}mail.med.upenn.edu

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_ARs), the major sites of fast synaptic inhibition in the brain. We demonstrate that SE selectively decreases the phosphorylation of GABA_ARs 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 patch-binding motif for the clathrin adaptor AP2, enhancing the endocytosis of selected GABA_AR 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 GABA_AR cell surface expression levels and restored the efficacy of synaptic inhibition in SE. Thus, enhancing phosphorylation of GABA_ARs or selectively blocking their interaction with AP2 may provide novel therapeutic strategies to ameliorate SE.

Key words: synaptic inhibition; protein kinase C; endocytosis; GABA_A receptor; phosphorylation; status epilepticus

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Received Sept. 21, 2007; revised Nov. 9, 2007; accepted Nov. 19, 2007.

Correspondence should be addressed to Stephen J. Moss at the above address. Email: sjmoss{at}mail.med.upenn.edu

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