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J. Biol. Chem., Vol. 279, Issue 8, 6967-6975, February 20, 2004

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Cross-talk and Co-trafficking between 1/GABA Receptors and ATP-gated Channels^*

Éric Boué-Grabot, Michel B. Émerit¶, Estelle Toulmé, Philippe Séguéla||, and Maurice Garret

From the CNRS Unité Mixte de Recherche 5543, Université Victor Segalen Bordeaux 2, 33076 Bordeaux cedex, France, ^¶INSERM U288, Hopital de la Salpétrière, 75013 Paris, France, and the ^||Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada

-Aminobutyric-acid (GABA) and ATP ionotropic receptors represent two structurally and functionally different classes of neurotransmitter-gated channels involved in fast synaptic transmission. We demonstrate here that, when the inhibitory 1/GABA and the excitatory P2X₂ receptor channels are co-expressed in Xenopus oocytes, activation of one channel reduces the currents mediated by the other one. This reciprocal inhibitory cross-talk is a receptor-mediated phenomenon independent of agonist cross-modulation, membrane potential, direction of ionic flux, or channel densities. Functional interaction is disrupted when the cytoplasmic C-terminal domain of P2X₂ is deleted or in competition experiments with minigenes coding for the C-terminal domain of P2X₂ or the main intracellular loop of 1 subunits. We also show a physical interaction between P2X₂ and 1 receptors expressed in oocytes and the co-clustering of these receptors in transfected hippocampal neurons. Co-expression with P2X₂ induces retargeting and recruitment of mainly intracellular 1/GABA receptors to surface clusters. Therefore, molecular and functional cross-talk between inhibitory and excitatory ligand-gated channels may regulate synaptic strength both by activity-dependent current occlusion and synaptic receptors co-trafficking.

Received for publication, July 18, 2003 , and in revised form, November 3, 2003.

^* This work was supported by grants from CNRS and Région Aquitaine (to E. B.-G. and M. G.), INSERM (to M. B. E.), and INSERM-Fonds de Recherche en Sante du Quebec (FRSQ) (to E. B.-G. and P. S.). 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.

To whom correspondence should be addressed: Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen Bordeaux 2, 33076 Bordeaux cedex, France. Tel.: 33-5-57-57-16-86; Fax: 33-5-56-90-14-21; E-mail: eric.boue-grabot{at}umr5543.u-bordeaux2.fr.

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