Abstract
ATP and gamma-aminobutyric acid (GABA) are two fast neurotransmitters co-released at central synapses, where they co-activate excitatory P2X and inhibitory GABAA (GABA type A) receptors. We report here that co-activation of P2X2 and various GABAA receptors, co-expressed in Xenopus oocytes, leads to a functional cross-inhibition dependent on GABAA subunit composition. Sequential applications of GABA and ATP revealed that alphabeta- or alphabetagamma-containing GABAA receptors inhibited P2X2 channels, whereas P2X2 channels failed to inhibit gamma-containing GABAA receptors. This functional cross-talk is independent of membrane potential, changes in current direction, and calcium. Non-additive responses observed between cation-selective GABAA 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 beta3 subunit disrupted the functional cross-inhibition. We previously demonstrated functional and physical cross-talk between rho1 and P2X2 receptors, which induced a retargeting of rho1 channels to surface clusters when co-expressed in hippocampal neurons (Boue-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 rho1 receptors with the C-terminal sequences of alpha2, beta3, or gamma2 subunits indicated that only rho1-beta3 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 beta GABAA subunits are required for the functional interaction between ATP- and GABA-gated channels. This gamma subunit-dependent cross-talk may contribute to the regulation of synaptic activity.
Highlights
Synaptic transmission is achieved through the release of one or more neurotransmitters from the same presynaptic terminal, resulting in the activation of different classes of receptors co-localized at the same post-synaptic site
We provide evidence in both Xenopus oocytes and transfected hippocampal neurons that molecular and functional interaction between P2X2 and GABAA receptors is a receptor-mediated phenomenon, dependent on GABAA subunit composition
Simultaneous application of ATP and GABA triggered an instantaneous current occlusion in oocytes co-expressing P2X2 and GABAA receptors containing various ␣ and  subunits, with or without ␥ subunits. These results showed that P2X2 channels interacted functionally with all major types of GABAA receptors
Summary
Synaptic transmission is achieved through the release of one or more neurotransmitters from the same presynaptic terminal, resulting in the activation of different classes of receptors co-localized at the same post-synaptic site. Cross-talk between distinct ligand-gated channels has been described between ATP P2X receptors and either acetylcholine nicotinic receptors (4 –7), 5-hydroxytryptamine 3 receptors [8, 9], or GABAA receptors in dorsal root ganglia neurons [10], as well as between GABA and glycine receptors in spinal cord neurons [11]. Because GABA and ATP are synaptically co-released in spinal cord and hypothalamic neurons [13, 14], where they activate co-localized ATP- and GABA-gated channels, cross-talk between inhibitory GABAA and excitatory P2X receptors may represent an important, fast process for controlling the signal transmission phenomenon. GABA-gated chloride channels mediate fast inhibition and play a fundamental role in the physiology and physiopathology of the nervous system [16] The diversity of their functional properties, pharmacology, and subcellular targeting depends to a large extent on subunit composition [16]. Little is known about purinergic transmission in the brain, despite the wide distribution of P2X receptor subunits throughout the central nervous system [19]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
