RT Journal Article SR Electronic T1 Propofol Restores the Function of “Hyperekplexic” Mutant Glycine Receptors in Xenopus Oocytes and Mice JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 2322 OP 2327 DO 10.1523/JNEUROSCI.4675-03.2004 VO 24 IS 9 A1 O'Shea, Sean Michael A1 Becker, Lore A1 Weiher, Hans A1 Betz, Heinrich A1 Laube, Bodo YR 2004 UL http://www.jneurosci.org/content/24/9/2322.abstract AB Human hereditary hyperekplexia (“startle disease”) is a neurological disorder characterized by exaggerated, convulsive movements in response to unexpected stimuli. Molecular genetic studies have shown that this disease is often caused by amino acid substitutions at arginine 271 to glutamine or leucine of the α1 subunit of the inhibitory glycine receptor (GlyR). When exogenously expressed in Xenopus oocytes, agonist responses of mutant α1(R271Q) and α1(R271L) GlyRs show higher EC50 values and lower maximal inducible responses (relative efficacies) compared with oocytes expressing wild-type α1 GlyR subunits. Here, we report that the maximal glycine-induced currents (Imax) of mutant α1(R271Q) and α1(R271L) GlyRs were dramatically potentiated in the presence of the anesthetic propofol (PRO), whereas the Imax of wild-type α1 receptors was not affected. Quantitative analysis of the agonist responses of the isofunctionally substituted α1(R271K) mutant GlyR revealed that saturating concentrations of PRO decreased the EC50 values of both glycine and the partial agonist β-alanine by >10-fold, with relative efficacies increasing by 4- and 16-fold, respectively. Transgenic (tg) mice carrying the α1(R271Q) mutation (tg271Q-300) have both spontaneous and induced tremor episodes that closely resemble the movements of startled hyperekplexic patients. After treatment with subanesthetic doses of PRO, the tg271Q-300 mutant mice showed temporary reflexive and locomotor improvements that made them indistinguishable from wild-type mice. Together, these results demonstrate that the functional and behavioral effects of hyperekplexia mutations can be effectively reversed by drugs that potentiate GlyR responses.