P2X7 RECEPTOR ACTIVATION DOWNMODULATES Na+-DEPENDENT HIGH- AFFINITY GABA AND GLUTAMATE TRANSPORT INTO RAT BRAIN CORTEX SYNAPTOSOMES

• Type: Article in International Scientific Journal
• Date: 2015

Authors

Barros Barbosa, AR (Author) Other; Lobo, MG (Author) ICBAS; Ferreirinha, F (Author) Other; Paulo Correia de Sá (Author) ICBAS; Cordeiro, JM (Author) Other

Journal

Title: Neuroscience

Vol. 306

Pages: 74-90

ISSN: 0306-4522

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 12 Citations

Scopus - 14 Citations

Other information

Authenticus ID: P-00G-JHX

DOI: 10.1016/j.neuroscience.2015.08.026

Abstract (EN): Sodium-dependent high-affinity amino-acid transporters play crucial roles in terminating synaptic transmission in the central nervous system (CNS). However, there is lack of information about the mechanisms underlying the regulation of amino-acid transport by fast-acting neuromodulators, like ATP. Here, we investigated whether activation of the ATP-sensitive P2X7 receptor modulates Na+-dependent high-affinity gamma-aminobutyric acid (GABA) and glutamate uptake into nerve terminals (synaptosomes) of the rat cerebral cortex. Radiolabeled neurotransmitter accumulation was evaluated by liquid scintillation spectrometry. The cell-permeant sodium-selective fluorescent indicator, SBFI-AM, was used to estimate Na+ influx across plasma membrane. 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP, 3-300 mu M), a prototypic P2X7 receptor agonist, concentration-dependently decreased [H-3] GABA (14%) and [C-14] glutamate (24%) uptake; BzATP decreased transport maximum velocity (V-max) without affecting the Michaelis constant (K-m) values. The selective P2X7 receptor antagonist, A-438079 (3 mu M), prevented inhibition of [H-3]GABA and [C-14]glutamate uptake by BzATP (100 mu M). The inhibitory effect of BzATP coincided with its ability to increase intracellular Na+ and was mimicked by Na+ ionophores, like gramicidin and monensin. Increases in intracellular Na+ (with veratridine or ouabain) or substitution of extracellular Na+ by N-methyl-D-glucamine (NMDG)(+) all decreased [H-3]GABA and [C-14]glutamate uptake and attenuated BzATP effects. Uptake inhibition by BzATP (100 mu M) was also attenuated by calmidazolium, which selectively inhibits Na+ currents through the P2X7 receptor pore. In conclusion, disruption of the Na+ gradient by P2X7 receptor activation downmodulates high-affinity GABA and glutamate uptake into rat cortical synaptosomes. Interference with amino-acid transport efficacy may constitute a novel target for therapeutic management of cortical excitability.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17