Propofol restores the function of hyperekplexic mutant glycine receptors in Xenopus oocytes and mice

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 alpha(1) subunit of the inhibitory glycine receptor ( GlyR). When exogenously expressed in Xenopus oocytes, agonist responses of mutant alpha(1)(R271Q) and alpha(1)(R271L) GlyRs show higher EC50 values and lower maximal inducible responses (relative efficacies) compared with oocytes expressing wild-type alpha(1) GlyR subunits. Here, we report that the maximal glycine-induced currents (I-max) of mutant alpha(1)(R271Q) and alpha(1)(R271L) GlyRs were dramatically potentiated in the presence of the anesthetic propofol (PRO), whereas the I-max of wild-type alpha(1) receptors was not affected. Quantitative analysis of the agonist responses of the isofunctionally substituted alpha(1)(R271K) mutant GlyR revealed that saturating concentrations of PRO decreased the EC50 values of both glycine and the partial agonist beta-alanine by >10-fold, with relative efficacies increasing by 4- and 16-fold, respectively. Transgenic (tg) mice carrying the alpha(1)(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.