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J. Biol. Chem., Vol. 282, Issue 22, 16016-16035, June 1, 2007

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Mechanisms for Picrotoxinin and Picrotin Blocks of ₂ Homomeric Glycine Receptors^*

Dian-Shi Wang¹, Roeland Buckinx^¶2, Hervé Lecorronc, Jean-Marie Mangin^||, Jean-Michel Rigo^¶, and Pascal Legendre³

From the UMR CNRS 7102 Neurobiologie des Processus Adaptatifs, Université Pierre et Marie Curie, 9 Quai St. Bernard, 75252, Paris Cedex 05, France, ^||Center for Neuroscience Research, Children's National Medical Center, Washington D. C. 20010, ^¶University Hasselt, Biomed Research Center, Agoralaan, B-3590 Diepenbeek, Belgium, and the Department of Anatomy, Fourth Military Medical University, Xi'an 710032, China

Contrary to its effect on the -aminobutyric acid type A and C receptors, picrotoxin antagonism of the ₁ homomeric glycine receptors (GlyRs) has been shown to be non-use-dependent and nonselective between the picrotoxin components picrotoxinin and picrotin. Picrotoxin antagonism of the embryonic ₂ homomeric GlyR is known to be use-dependent and reflects a channel-blocking mechanism, but the selectivity of picrotoxin antagonism of the embryonic ₂ homomeric GlyRs between picrotoxinin and picrotin is unknown. Hence, we used the patch clamp recording technique in the outside-out configuration to investigate, at the single channel level, the mechanism of picrotin- and picrotoxinin-induced inhibition of currents, which were evoked by the activation of ₂ homomeric GlyRs stably transfected into Chinese hamster ovary cells. Although both picrotoxinin and picrotin inhibited glycine-evoked outside-out currents, picrotin had a 30 times higher IC₅₀ than picrotoxinin. Picrotin-evoked inhibition displayed voltage dependence, whereas picrotoxinin did not. Picrotoxinin and picrotin decreased the mean open time of the channel in a concentration-dependent manner, indicating that these picrotoxin components can bind to the receptor in its open state. When picrotin and glycine were co-applied, a large rebound current was observed at the end of the application. This rebound current was considerably smaller when picrotoxinin and glycine were co-applied. Both picrotin and picrotoxinin were unable to bind to the unbound conformation of the receptor, but both could be trapped at their binding site when the channel closed during glycine dissociation. Our data indicate that picrotoxinin and picrotin are not equivalent in blocking ₂ homomeric GlyR.

Received for publication, February 20, 2007 , and in revised form, March 27, 2007.

^* This work was supported in part by INSERM, CNRS, Association Française Contre les Myopathies, and INSERM-MVG agreement (to P. L. and J.-M. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ On leave from the Dept. of Anatomy, Fourth Military Medical University, Xi'an 710032, China, and is supported by a Human Frontier Science Program Short Term Fellowship and an International Brain Research Organization Research Fellowship.

² Supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen).

³ To whom correspondence should be addressed: UMR CNRS 7102, NPA, Université Pierre et Marie Curie, Batiment B, 6Étage, Case 1, 9 Quai St. Bernard, 75252 Paris Cedex 05, France. Tel.: 33-1-44-27-25-19; Fax: 33-1-44-27-27-81; E-mail: pascal.legendre{at}snv.jussieu.fr.

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