Cross-talk between P2X4 and gamma-aminobutyric acid, type A receptors determines synaptic efficacy at a central synapse.
J. Biol. Chem.. 2011-04-11; 286(22): 19993-20004
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1. J Biol Chem. 2011 Jun 3;286(22):19993-20004. doi: 10.1074/jbc.M111.231324. Epub
2011 Apr 11.
Cross-talk between P2X4 and gamma-aminobutyric acid, type A receptors determines
synaptic efficacy at a central synapse.
Jo YH(1), Donier E, Martinez A, Garret M, Toulmé E, Boué-Grabot E.
(1)Department of Medicine, Albert Einstein College of Medicine, Bronx, New York
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 (GABA(A)) receptors and
demonstrate that two amino acids in the carboxyl tail of the P2X4 subunit are
crucial for its physical association with GABA(A) receptors. Mutation of these
two residues prevents the physical association, thereby blocking cross-inhibition
between P2X4 and GABA(A) receptors. Moreover, disruption of the physical coupling
using competitive peptides containing the identified motif abolishes current
inhibition between P2X4 and GABA(A) 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.
PMID: 21482824 [Indexed for MEDLINE]