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The Journal of Neuroscience, September 27, 2006, 26(39):10033-10042; doi:10.1523/JNEUROSCI.2750-06.2006

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Neurobiology of Disease
Interface Interactions Modulating Desensitization of the Kainate-Selective Ionotropic Glutamate Receptor Subunit GluR6

Yihong Zhang,¹ Naushaba Nayeem,¹ Max H. Nanao,² and Tim Green¹

¹Department of Pharmacology, School of Biomedical Sciences, University of Liverpool, Liverpool L69 3GE, United Kingdom, and ²Exelixis Inc., South San Francisco, California 94083

Correspondence should be addressed to Tim Green, Department of Pharmacology, School of Biomedical Sciences, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. Email: tpgreen{at}liv.ac.uk

Ionotropic glutamate receptors from the AMPA and kainate subfamilies share many functional and structural features, but it is unclear whether this similarity extends to the molecular mechanisms underlying receptor desensitization. The current model for desensitization in AMPA receptors involves the rearrangement of dimers formed between subunit agonist binding domains. Key evidence for this has come from a single point mutant (from leucine to tyrosine) that abolished desensitization and that was shown to stabilize the binding domain dimer. However, the desensitization of kainate receptors appears to differ from that of AMPA receptors in several key respects. Although the kinetics of AMPA receptor gating and desensitization are consistent with channels formed from two dimers, similar evidence for the functional involvement of dimers has not been found in kainate receptors. Furthermore, despite the homolog of the nondesensitizing tyrosine in AMPA subunits also being a tyrosine in wild-type kainate subunits, these receptors desensitize rapidly and completely. Using mutagenesis based on the crystal structure of the glutamate receptor subunit GluR6 S1S2 domain in complex with domoate, we identified four residues neighboring this tyrosine that differ between AMPA and kainate subunits and that contribute to the different desensitization kinetics of these receptors. Detailed analysis of the effects of mutations at these sites confirms that there is in fact a common general mechanism for desensitization in non-NMDA receptors, dependent on the stability of the binding domain dimer interface, and reveals the existence of potential agonist-specific desensitization pathways.

Key words: glutamate; kainate receptor; desensitization; S1S2 domain; dimer interface; mutagenesis

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Received April 28, 2006; revised Aug. 21, 2006; accepted Aug. 22, 2006.

Correspondence should be addressed to Tim Green, Department of Pharmacology, School of Biomedical Sciences, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. Email: tpgreen{at}liv.ac.uk

This article has been cited by other articles:

				Y. Zhang, N. Nayeem, and T. Green Mutations to the Kainate Receptor Subunit GluR6 Binding Pocket That Selectively Affect Domoate Binding Mol. Pharmacol., October 1, 2008; 74(4): 1163 - 1169. [Abstract] [Full Text] [PDF]

				P. Vivithanaporn, L. L. Lash, W. Marszalec, and G. T. Swanson Critical Roles for the M3 S2 Transduction Linker Domain in Kainate Receptor Assembly and Postassembly Trafficking J. Neurosci., September 26, 2007; 27(39): 10423 - 10433. [Abstract] [Full Text] [PDF]

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