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J. Biol. Chem., Vol. 279, Issue 50, 52517-52525, December 10, 2004

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Subunit-specific Coupling between -Aminobutyric Acid Type A and P2X₂ Receptor Channels^*

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

From the Laboratoire de Neurophysiologie, CNRS Unité Miate de Recherche UMR 5543, Université Victor Segalen Bordeaux 2, 33076 Bordeaux cedex and ^||INSERM U288, Hopital de la Salpétrière, 75013 Paris, France

ATP and -aminobutyric acid (GABA) are two fast neurotransmitters co-released at central synapses, where they co-activate excitatory P2X and inhibitory GABA_A (GABA type A) receptors. We report here that co-activation of P2X₂ and various GABA_A receptors, co-expressed in Xenopus oocytes, leads to a functional cross-inhibition dependent on GABA_A subunit composition. Sequential applications of GABA and ATP revealed that - or -containing GABA_A receptors inhibited P2X₂ channels, whereas P2X₂ channels failed to inhibit -containing GABA_A receptors. This functional cross-talk is independent of membrane potential, changes in current direction, and calcium. Non-additive responses observed between cation-selective GABA_A and P2X₂ receptors further indicate the chloride independence of this process. Overexpression of minigenes encoding either the C-terminal fragment of P2X₂ or the intracellular loop of the 3 subunit disrupted the functional cross-inhibition. We previously demonstrated functional and physical cross-talk between 1 and P2X₂ receptors, which induced a retargeting of 1 channels to surface clusters when co-expressed in hippocampal neurons (Boué-Grabot, E., Emerit, M. B., Toulme, E., Seguela, P., and Garret, M. (2004) J. Biol. Chem. 279, 6967–6975). Co-expression of P2X₂ and chimeric 1 receptors with the C-terminal sequences of 2, 3, or 2 subunits indicated that only 1-3 and P2X₂ channels exhibit both functional cross-inhibition in Xenopus oocytes and co-clustering/retargeting in hippocampal neurons. Therefore, the C-terminal domain of P2X₂ and the intracellular loop of GABA_A subunits are required for the functional interaction between ATP- and GABA-gated channels. This subunit-dependent cross-talk may contribute to the regulation of synaptic activity.

Received for publication, September 7, 2004

^* This work was supported in part by CNRS, Region Aquitaine, and Université Victor Segalen de Bordeaux2 (to E. B. G. and M. G.) and INSERM (to M. B. E.). 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.

^¶ Recipient of a post graduate fellowship from the Ministère de l'Education Nationale et de la Recherche.

To whom correspondence should be addressed. Tel.: 33-(0)5-5757-1686; Fax: 33-(0)5-5690-1421; E-mail: eric.boue-grabot{at}umr5543.u-bordeaux2.fr.

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