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The Journal of Neuroscience, October 15, 1999, 19(20):8757-8764

Generation and Analysis of GluR5(Q636R) Kainate Receptor Mutant Mice

Andreas Sailer¹, Geoffrey T. Swanson¹, Isabel Pérez-Otaño¹, Lora O'Leary¹, Shelle A. Malkmus⁴, Richard H. Dyck¹, Heather Dickinson-Anson³, Hans H. Schiffer¹, Cornelia Maron¹, Tony L. Yaksh⁴, Fred H. Gage³, Stephen O'Gorman², and Stephen F. Heinemann¹

¹  Molecular Neurobiology Laboratory, ² Gene Expression Laboratory, and ³ Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, and ⁴ Department of Pharmacology and Anesthesiology, University of California, San Diego, La Jolla, California 92093

The physiological significance of RNA editing of transcripts that code for kainate-preferring glutamate receptor subunits is unknown, despite the fact that the functional consequences of this molecular modification have been well characterized in cloned receptor subunits. RNA editing of the codon that encodes the glutamine/arginine (Q/R) site in the second membrane domain (MD2) of glutamate receptor 5 (GluR5) and GluR6 kainate receptor subunits produces receptors with reduced calcium permeabilities and single-channel conductances. Approximately 50% of the GluR5 subunit transcripts from adult rat brain are edited at the Q/R site in MD2. To address the role of glutamate receptor mRNA editing in the brain, we have made two strains of mice with mutations at amino acid 636, the Q/R-editing site in GluR5, using embryonic stem cell-mediated transgenesis. GluR5(R^loxP/R^loxP) mice encode an arginine at the Q/R site of the GluR5 subunit, whereas GluR5(wt^loxP/wt^loxP) mice encode a glutamine at this site, similar to wild-type mice. Mutant animals do not exhibit developmental abnormalities, nor do they show deficits in the behavioral paradigms tested in this study. Kainate receptor current densities were reduced by a factor of six in acutely isolated sensory neurons of dorsal root ganglia from GluR5(R^loxP/R^loxP) mice compared with neurons from wild-type mice. However, the editing mutant mice did not exhibit altered responses to thermal and chemical pain stimuli. Our investigations with the GluR5-editing mutant mice have therefore defined a set of physiological processes in which editing of the GluR5 subunit is unlikely to play an important role.

Key words: RNA editing; glutamate receptor; pain; dorsal root ganglia; gene targeting; Cre recombinase

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19208757-08$05.00/0

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