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

• Published in: The Journal of biological chemistry Vol. 279; no. 50; p. 52517
• Main Authors: Éric Boué-Grabot, Estelle ToulmÃ, Michel B. Émerit, Maurice Garret
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 10.12.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M410223200

ATP and γ-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 P2X 2 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 αβ- or αβγ-containing GABA A receptors inhibited P2X 2 channels, whereas P2X 2 channels failed to inhibit γ-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 P2X 2 receptors further indicate the chloride independence of this process. Overexpression of minigenes encoding either the C-terminal fragment of P2X 2 or the intracellular loop of the β3 subunit disrupted the functional cross-inhibition. We previously demonstrated functional and physical cross-talk between ρ1 and P2X 2 receptors, which induced a retargeting of ρ1 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 P2X 2 and chimeric ρ1 receptors with the C-terminal sequences of α2, β3, or γ2 subunits indicated that only ρ1-β3 and P2X 2 channels exhibit both functional cross-inhibition in Xenopus oocytes and co-clustering/retargeting in hippocampal neurons. Therefore, the C-terminal domain of P2X 2 and the intracellular loop of β GABA A subunits are required for the functional interaction between ATP- and GABA-gated channels. This γ subunit-dependent cross-talk may contribute to the regulation of synaptic activity.