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The Journal of Neuroscience, February 6, 2008, 28(6):1356-1365; doi:10.1523/JNEUROSCI.5050-07.2008

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Cellular/Molecular
The Clustering of GABA_A Receptor Subtypes at Inhibitory Synapses is Facilitated via the Direct Binding of Receptor 2 Subunits to Gephyrin

Verena Tretter,^1,2 Tija C. Jacob,^1,2 Jayanta Mukherjee,¹ Jean-Marc Fritschy,³ 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, ³University of Zurich, Institute of Pharmacology and Toxicology, CH-8057 Zurich, Switzerland, 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

Classical benzodiazepine sensitive GABA_A receptor subtypes, the major mediators of fast synaptic inhibition in the brain are heteropentamers that can be assembled from 1–3/5, β1–3, and 2 subunits, but how neurons orchestrate their selective accumulation at synapses remains obscure. We have identified a 10 amino acid hydrophobic motif within the intracellular domain of the 2 subunit that regulates the accumulation of GABA_A receptors at inhibitory synaptic sites on both axon initial segments and dendrites in a mechanism dependent on the inhibitory scaffold protein gephyrin. This motif was sufficient to target CD4 (cluster of differentiation molecule 4) molecules to inhibitory synapses, and was also critical in regulating the direct binding of 2 subunits to gephyrin in vitro. Our results thus reveal that the specific accumulation of GABA_A receptor subtypes containing 2 subunits at inhibitory synapses is dependent on their ability to bind gephyrin.

Key words: GABA_A receptor; gephyrin; synaptogenesis; CD4; clustering; GABA_A receptor trafficking

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Received Sept. 5, 2007; revised Dec. 6, 2007; accepted Dec. 10, 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:

				M. Calamai, C. G. Specht, J. Heller, D. Alcor, P. Machado, C. Vannier, and A. Triller Gephyrin Oligomerization Controls GlyR Mobility and Synaptic Clustering J. Neurosci., June 17, 2009; 29(24): 7639 - 7648. [Abstract] [Full Text] [PDF]

				B. Smolinsky, S. A. Eichler, S. Buchmeier, J. C. Meier, and G. Schwarz Splice-specific Functions of Gephyrin in Molybdenum Cofactor Biosynthesis J. Biol. Chem., June 20, 2008; 283(25): 17370 - 17379. [Abstract] [Full Text] [PDF]

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