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

• Published in: The Journal of neuroscience 1999-10, Vol.19 (20), p.8757-8764
• Main Authors: Sailer, Andreas, Swanson, Geoffrey T, Perez-Otano, Isabel, O'Leary, Lora, Malkmus, Shelle A, Dyck, Richard H, Dickinson-Anson, Heather, Schiffer, Hans H, Maron, Cornelia, Yaksh, Tony L, Gage, Fred H, O'Gorman, Stephen, Heinemann, Stephen F
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal; Electrophysiology; Ganglia, Spinal - cytology; Ganglia, Spinal - metabolism; Kainic Acid; kainic acid receptors; Mice; Mice, Mutant Strains - genetics; Mice, Mutant Strains - physiology; Mice, Mutant Strains - psychology; Neurons - metabolism; Pain - psychology; Receptors, Kainic Acid - metabolism; Recombination, Genetic; Reference Values; Seizures - chemically induced
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.19-20-08757.1999

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(RloxP/RloxP) 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(RloxP/RloxP) 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.