Cross-talk between P2X4 and γ-aminobutyric acid, type A receptors determines synaptic efficacy at a central synapse

Young-Hwan Jo, Emmanuelle Donier, Audrey Martinez, Maurice Garret, Estelle Toulmé, Eric Boué-Grabot

Research output: Contribution to journalArticle

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Abstract

The essence of neuronal function is to generate outputs in response to synaptic potentials. Synaptic integration at postsynaptic sites determines neuronal outputs in the CNS. Using immunohistochemical and electrophysiological approaches, we first reveal that steroidogenic factor 1 (SF-1) green fluorescent protein (GFP)-positive neurons in the ventromedial nucleus of the hypothalamus express P2X4 subunits that are activated by exogenous ATP. Increased membrane expression of P2X4 channels by using a peptide competing with P2X4 intracellular endocytosis motif enhances neuronal excitability of SF-1 GFP-positive neurons. This increased excitability is inhibited by a P2X receptor antagonist. Furthermore, increased surface P2X4 receptor expression significantly decreases the frequency and the amplitude of GABAergic postsynaptic currents of SF-1 GFP-positive neurons. Co-immunopurification and pulldown assays reveal that P2X4 receptors complex with aminobutyric acid, type A (GABAA) receptors and demonstrate that two amino acids in the carboxyl tail of the P2X4 subunit are crucial for its physical association with GABAA receptors. Mutation of these two residues prevents the physical association, thereby blocking cross-inhibition between P2X4 and GABAA receptors. Moreover, disruption of the physical coupling using competitive peptides containing the identified motif abolishes current inhibition between P2X4 and GABAA receptors in recombinant system and P2X4 receptor-mediated GABAergic depression in SF-1 GFP-positive neurons. Our present work thus provides evidence for cross-talk between excitatory and inhibitory receptors that appears to be crucial in determining GABAergic synaptic strength at a central synapse.

Original languageEnglish (US)
Pages (from-to)19993-20004
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number22
DOIs
StatePublished - Jun 3 2011

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Purinergic P2X4 Receptors
Aminobutyrates
Neurotransmitter Receptor
Steroidogenic Factor 1
Synapses
GABA-A Receptors
Green Fluorescent Proteins
Neurons
Synaptic Potentials
Association reactions
Peptides
Endocytosis
Hypothalamus
Assays
Adenosine Triphosphate
Membranes
Amino Acids
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cross-talk between P2X4 and γ-aminobutyric acid, type A receptors determines synaptic efficacy at a central synapse. / Jo, Young-Hwan; Donier, Emmanuelle; Martinez, Audrey; Garret, Maurice; Toulmé, Estelle; Boué-Grabot, Eric.

In: Journal of Biological Chemistry, Vol. 286, No. 22, 03.06.2011, p. 19993-20004.

Research output: Contribution to journalArticle

Jo, Young-Hwan ; Donier, Emmanuelle ; Martinez, Audrey ; Garret, Maurice ; Toulmé, Estelle ; Boué-Grabot, Eric. / Cross-talk between P2X4 and γ-aminobutyric acid, type A receptors determines synaptic efficacy at a central synapse. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 22. pp. 19993-20004.
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