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J. Biol. Chem., Vol. 281, Issue 7, 3841-3855, February 17, 2006

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Mechanisms for Picrotoxin Block of ₂ Homomeric Glycine Receptors^*

Dian-Shi Wang¹, Jean-Marie Mangin^¶, Gustave Moonen^¶, Jean-Michel Rigo^¶||, and Pascal Legendre²

From the Unité Mixte de Recherche, CNRS 7102, Neurobiologie des Processus Adaptatifs, Université Pierre et Marie Curie, 9 Quai St. Bernard, 75252, Paris cedex 05, France, the ^¶FacultédeMédecine de Liège, Centre de Recherche en Neurobiologie Cellulaire et Moléculaire, 17 place Delcour, B-4020 Liège 2, Belgium, the ^||Biomed Research Center, Universiteit Hasselt, Agoralaan, B-3590 Diepenbeek, Belgium, and the Department of Anatomy, Fourth Military Medical University, Xi'an 710032, China

It is well known that the convulsant alkaloid picrotoxin (PTX) can inhibit neuronal -aminobutyric acid (GABA) and homomeric glycine receptors (GlyR). However, the mechanism for PTX block of ₂ homomeric GlyR is still unclear compared with that of ₁ homomeric GlyR, GABA_A, and GABA_C receptors. Furthermore, PTX effects on GlyR kinetics have been poorly explored at the single-channel level. Hence, we used the patch-clamp technique in the outside-out configuration to investigate the mechanism of PTX suppression of currents carried by ₂ homomeric GlyRs stably transfected into Chinese hamster ovary cells. PTX inhibited the ₂ homomeric GlyR current elicited by glycine in a concentration-dependent and voltage-independent manner. Both competitive and noncompetitive mechanisms were observed. PTX decreased the mean open time of the GlyR channel in a concentration-dependent manner, suggesting that PTX can block channel openings and bind to the receptor in the open channel conformation. When PTX and glycine were co-applied, a small rebound current was observed during drug washout. Application of PTX during the deactivation phase of glycine-induced currents eliminated the rebound current and accelerated the deactivation time course in a concentration-dependent manner. PTX could not bind to the unbound conformation of GlyR, but could be trapped at its binding site when the channel closed during glycine dissociation. Based on these observations, we propose a kinetic Markov model in which PTX binds to the ₂ homomeric GlyR in both the open channel state and the fully liganded closed state. Our data suggest a new allosteric mechanism for PTX inhibition of wild-type homomeric ₂ GlyR.

Received for publication, October 11, 2005 , and in revised form, December 12, 2005.

^* This work was supported in part by INSERM, CNRS, NRJ funding, Association Française contre les Myopathies, and INSERM-Communauté Française de Belgique agreement (to P. L. and J.-M. Rigo). 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 Supported by the Human Frontier Science Program Short-Term Fellowship and International Brain Research Organization Research Fellowship.

² To whom correspondence should be addressed. Tel.: 44-27-25-19; Fax: 44-27-27-81; E-mail: pascal.legendre{at}snv.jussieu.fr.

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