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The Journal of Neuroscience, November 28, 2007, 27(48):13341-13351; doi:10.1523/JNEUROSCI.3277-07.2007

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Cellular/Molecular
Activity-Dependent Ubiquitination of GABA_A Receptors Regulates Their Accumulation at Synaptic Sites

Richard S. Saliba,^1,2 Guido Michels,^1,3 Tija C. Jacob,¹ Menelas N. Pangalos,⁴ and Stephen J. Moss^1,2

¹Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, ²Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, ³Department of Internal Medicine III, University of Cologne, 50937 Cologne, Germany, and ⁴Wyeth Research, Neuroscience Discovery, Princeton, New Jersey 08852

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

GABA_A receptors (GABA_ARs) are the major mediators of fast synaptic inhibition in the brain. In neurons, these receptors undergo significant rates of endocytosis and exocytosis, processes that regulate both their accumulation at synaptic sites and the efficacy of synaptic inhibition. Here we have evaluated the role that neuronal activity plays in regulating the residence time of GABA_ARs on the plasma membrane and their targeting to synapses. Chronic blockade of neuronal activity dramatically increases the level of the GABA_AR ubiquitination, decreasing their cell surface stability via a mechanism dependent on the activity of the proteasome. Coincident with this loss of cell surface expression levels, TTX treatment reduced both the amplitude and frequency of miniature inhibitory synaptic currents. Conversely, increasing the level of neuronal activity decreases GABA_AR ubiquitination enhancing their stability on the plasma membrane. Activity-dependent ubiquitination primarily acts to reduce GABA_AR stability within the endoplasmic reticulum and, thereby, their insertion into the plasma membrane and subsequent accumulation at synaptic sites. Thus, activity-dependent ubiquitination of GABA_ARs and their subsequent proteasomal degradation may represent a potent mechanism to regulate the efficacy of synaptic inhibition and may also contribute to homeostatic synaptic plasticity.

Key words: GABA_A receptor; ubiquitination; synapse; proteasome; membrane insertion; inhibition

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Received July 19, 2007; revised Oct. 17, 2007; accepted Oct. 22, 2007.

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

This article has been cited by other articles:

				B. K. Andrasfalvy, J. K. Makara, D. Johnston, and J. C. Magee Altered synaptic and non-synaptic properties of CA1 pyramidal neurons in Kv4.2 knockout mice J. Physiol., August 15, 2008; 586(16): 3881 - 3892. [Abstract] [Full Text] [PDF]

				R. S. Saliba, M. Pangalos, and S. J. Moss The Ubiquitin-like Protein Plic-1 Enhances the Membrane Insertion of GABAA Receptors by Increasing Their Stability within the Endoplasmic Reticulum J. Biol. Chem., July 4, 2008; 283(27): 18538 - 18544. [Abstract] [Full Text] [PDF]

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