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J. Biol. Chem., Vol. 282, Issue 26, 18758-18766, June 29, 2007

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Stargazin Interaction with -Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA) Receptors Is Critically Dependent on the Amino Acid at the Narrow Constriction of the Ion Channel^*

Christoph Körber, Markus Werner, Jutta Hoffmann¹, Charlotte Sager, Monique Tietze, Sabine M. Schmid^¶2, Sabine Kott, and Michael Hollmann^¶3

From the Department of Biochemistry I-Receptor Biochemistry, Ruhr University Bochum, D-44780 Bochum, Germany, Graduiertenkolleg 736, Deutsche Forschungsgemeinschaft, D-44780 Bochum, Germany, and the ^¶International Graduate School of Neuroscience, D-44780 Bochum, Germany

The subunit GluR2 of the -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subfamily of ionotropic glutamate receptors (GluRs) features a single amino acid at the narrow constriction of the pore loop that is altered from glutamine to arginine by RNA editing. This so-called Q/R site has been shown to play an important role in the determination of the electrophysiological properties of AMPA receptor complexes as well as of trafficking to the plasma membrane. The protein stargazin has also been shown to modulate electrophysiological properties and trafficking to the plasma membrane of AMPA receptors. In this study we examined via a series of mutants of the Q/R site of the AMPA receptor GluR1 whether the amino acid at this position has any influence on the modulatory effects mediated by stargazin. To this end, we analyzed current responses of Q/R site mutants upon application of glutamate and kainate and determined the amount of mutant receptor protein in the plasma membrane in Xenopus oocytes. Desensitization kinetics of several mutants were analyzed in HEK293 cells. We found that the stargazin-mediated decrease in receptor desensitization, the slowing of desensitization kinetics, and the kainate efficacy were all dependent on the amino acid at the Q/R site, whereas the stargazin-mediated increase in trafficking toward the plasma membrane remained independent of this amino acid. We propose that the Q/R site modulates the interaction of stargazin with the transmembrane domains of AMPA receptors via an allosteric mechanism and that this modulation leads to the observed differences in the electrophysiological properties of the receptor.

Received for publication, December 6, 2006 , and in revised form, April 19, 2007.

^* This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (DFG) (to M. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Graduiertenkolleg 736 "Development and Plasticity of the Nervous System" from the DFG.

² Supported by the International Graduate School of Neuroscience, Ruhr University Bochum.

³ To whom correspondence should be addressed: Dept. of Biochemistry I-Receptor Biochemistry, Bldg. NC, Level 6, Rm. 170, D-44780 Bochum, Germany. Tel.: 49-234-322-4225; Fax: 49-234-321-4244; E-mail: Michael.Hollmann{at}rub.de.

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