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The Journal of Neuroscience, March 3, 2004, 24(9):2322-2327; doi:10.1523/JNEUROSCI.4675-03.2004

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Propofol Restores the Function of "Hyperekplexic" Mutant Glycine Receptors in Xenopus Oocytes and Mice

Sean Michael O'Shea,¹ Lore Becker,² Hans Weiher,² Heinrich Betz,¹ and Bodo Laube¹

¹Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, 60528 Frankfurt am Main, Germany, and ²Institute for Diabetes Research, 80804 Munich, Germany

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

Key words: anesthesia; glycine; inhibition; IPSP (inhibitory potential); receptor; startle

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Received Oct 16, 2003; revised January 13, 2004; accepted January 14, 2004.

This article has been cited by other articles:

				S. M. O'Shea, C. A. Williams, and A. Jenkins Inverse Effects on Gating and Modulation Caused by a Mutation in the M2-M3 Linker of the GABAA Receptor {gamma} Subunit Mol. Pharmacol., September 1, 2009; 76(3): 641 - 651. [Abstract] [Full Text] [PDF]

				J. Ahrens, M. Leuwer, S. Stachura, K. Krampfl, D. Belelli, J. J. Lambert, and G. Haeseler A Transmembrane Residue Influences the Interaction of Propofol with the Strychnine-Sensitive Glycine {alpha}1 and {alpha}1{beta} Receptor Anesth. Analg., December 1, 2008; 107(6): 1875 - 1883. [Abstract] [Full Text] [PDF]

				S. A. Pless, M. I. Dibas, H. A. Lester, and J. W. Lynch Conformational Variability of the Glycine Receptor M2 Domain in Response to Activation by Different Agonists J. Biol. Chem., December 7, 2007; 282(49): 36057 - 36067. [Abstract] [Full Text] [PDF]

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