P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes

Barros‐Barbosa, Aurora; Lobo, M. Graça; Ferreirinha, Fátima; Correia-de-Sá, Paulo; Cordeiro, Miguel

doi:10.1016/j.neuroscience.2015.08.026

Cited by 19 publications

(29 citation statements)

References 66 publications

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“…[ 3 H]GABA uptake was measured as described elsewhere . [ 3 H]GABA (0.25 μCi/ml; 0.5 μ m ) uptake reactions, carried out at 30°C, were initiated by adding either synaptosomes or resealed nerve terminal membranes to the reaction media containing AOAA, which prevents GABA metabolism by GABA transaminase.…”

Section: Methodsmentioning

confidence: 99%

“…Given our previous study showing that the P2X7R activation down‐modulates Na + ‐dependent high‐affinity GABA and glutamate transport into rat brain cortical synaptosomes, here we investigated if this modulation also occurs in the neocortex of cadaveric controls and epileptic (non‐MTLE and MTLE) human patients. Taking into consideration the overall antagonistic effects of GABA and glutamate on synaptic networking, the uptake of the two amino acids was evaluated in parallel, that is, under the same modulatory conditions, in order to appreciate putative differential effects caused by activation of the P2X7R in control and epileptic tissue.…”

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confidence: 99%

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Up‐regulation of P2X7 receptor–mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex

et al. 2015

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Summary Objective Thirty percent of patients with epilepsy are refractory to medication. The majority of these patients have mesial temporal lobe epilepsy (MTLE). This prompts for new pharmacologic targets, like ATP‐mediated signaling pathways, since the extracellular levels of the nucleotide dramatically increase during in vitro epileptic seizures. In this study, we investigated whether sodium‐dependent high‐affinity γ‐aminobutyric acid (GABA) and glutamate uptake by isolated nerve terminals of the human neocortex could be modulated by ATP acting via slow‐desensitizing P2X7 receptor (P2X7R). Methods Modulation of [3H]GABA and [14C]glutamate uptake by ATP, through activation of P2X7R, was investigated in isolated nerve terminals of the neocortex of cadaveric controls and patients with drug‐resistant epilepsy (non‐MTLE or MTLE) submitted to surgery. Tissue density and distribution of P2X7R in the human neocortex was assessed by Western blot analysis and immunofluorescence confocal microscopy. Results The P2X7R agonist, 2′(3′)‐O‐(4‐benzoylbenzoyl)ATP (BzATP, 3–100 μm) decreased [3H]GABA and [14C]glutamate uptake by nerve terminals of the neocortex of controls and patients with epilepsy. The inhibitory effect of BzATP (100 μm) was prevented by the selective P2X7R antagonist, A‐438079 (3 μm). Down‐modulation of [14C]glutamate uptake by BzATP (100 μm) was roughly similar in controls and patients with epilepsy, but the P2X7R agonist inhibited more effectively [3H]GABA uptake in the epileptic tissue. Neocortical nerve terminals of patients with epilepsy express higher amounts of the P2X7R protein than control samples. Significance High‐frequency cortical activity during epileptic seizures releases huge amounts of ATP, which by acting on low‐affinity slowly desensitizing ionotropic P2X7R, leads to down‐modulation of neuronal GABA and glutamate uptake. Increased P2X7R expression in neocortical nerve terminals of patients with epilepsy may, under high‐frequency firing, endure GABA signaling and increase GABAergic rundown, thereby unbalancing glutamatergic neuroexcitation. This study highlights the relevance of the ATP‐sensitive P2X7R as an important negative modulator of GABA and glutamate transport and prompts for novel antiepileptic therapeutic targets.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Up‐regulation of P2X7 receptor–mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex

et al. 2015

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“…While activation of P2YRs is mainly coupled to phospholipase C (PLC), activation of the ionotropic P2XRs cause the opening of cation permeable channels, initiating intracellular Ca 2+ mobilization and further downstream signaling 3, 4 . Among all P2X receptors, the P2X7 receptor (P2X7R) is a well-defined therapeutic target for inflammatory diseases 5 , and has been found in the central and peripheral nervous systems 6–8 . Specifically, P2X7R is known to be involved in cell proliferation, apoptosis, modulation of neurotransmitter release, and microglial and astrocyte activation in the nervous system 9, 10 .…”

Section: Introductionmentioning

confidence: 99%

Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice

Muñoz

Gao

Tian

et al. 2017

Sci Rep

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ATP can activate a variety of pathways through P2 purinoreceptors, leading to neuroprotection and pathology in the CNS. Among all P2X receptors, the P2X7 receptor (P2X7R) is a well-defined therapeutic target for inflammatory and neuropathic pain. Activation of P2X7R can generate reactive oxygen species (ROS) in macrophages and microglia. However, the role of ROS in P2X7R–induced pain remains unexplored. Here, we investigated the downstream effects of neuronal P2X7R activation in the spinal cord. We found that ATP induces ROS production in spinal cord dorsal horn neurons, an effect eliminated by ROS scavenger N-tert-butyl-α-phenylnitrone (PBN) and P2X7R antagonist A438079. A similar effect was observed with a P2X7R agonist, BzATP, and was attenuated by a NADPH oxidase inhibitor apocynin. Intrathecal administration of BzATP resulted in ROS production in the spinal cord and oxidative DNA damage in dorsal horn neurons. BzATP also induced robust biphasic spontaneous nociceptive behavior. Pre-treatment with A438079 abolished all BzATP-induced nociceptive behaviors, while ROS scavengers dose-dependently attenuated the secondary response. Here, we provide evidence that neuronal P2X7R activation leads to ROS production and subsequent nociceptive pain in mice. Together, the data indicate that P2X7R-induced ROS play a critical role in the P2X7R signaling pathway of the CNS.

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“…In accordance with these functions, P2X 7 receptors are widely distributed in immunocompetent cells and glial cells of the central and peripheral nervous systems, as well as in smooth muscles (Collo et al, ; Sperlágh et al, ; Svennersten et al, ). Moreover, P2X 7 receptors also regulate the release of neurotransmitters, IL‐1β, TNF‐α, prostaglandin E2 (PGE2), astroglial activation, and microglial activation (Ferrari et al, ; Suzuki et al, ; Sperlágh et al, ; Barbera‐Cremades et al, ; Ficker et al, ; Barros‐Barbosa et al, ; Del Puerto et al, ; Di Cesare Mannelli et al, ; Toki et al, ). On immunocompetent cells, these receptors modulate the expression and secretion of cytokines and inflammatory mediators and regulate the direct effector functions (Sperlágh et al, ).…”

Section: Function and Location Of P2x Receptorsmentioning

confidence: 99%

Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X₂in the Auditory System

et al. 2015

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The P2X purinergic receptors are cation-selective channels gated by extracellular adenosine 5'-triphosphate (ATP). These purinergic receptors are found in virtually all mammalian cell types and facilitate a number of important physiological processes. Within the past few years, the characterization of crystal structures of the zebrafish P2X4 receptor in its closed and open states has provided critical insights into the mechanisms of ligand binding and channel activation. Understanding of this gating mechanism has facilitated to design and interpret new modeling and structure-function experiments to better elucidate how different agonists and antagonists can affect the receptor with differing levels of potency. This review summarizes the current knowledge on the structure, activation, allosteric modulators, function, and location of the different P2X receptors. Moreover, an emphasis on the P2X2 receptors has been placed in respect to its role in the auditory system. In particular, the discovery of three missense mutations in P2X2 receptors could become important areas of study in the field of gene therapy to treat progressive and noise-induced hearing loss. J. Cell. Physiol. 231: 1656-1670, 2016. © 2015 Wiley Periodicals, Inc.

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P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes

Cited by 19 publications

References 66 publications

Up‐regulation of P2X7 receptor–mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex

Up‐regulation of P2X7 receptor–mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex

Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice

Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X₂in the Auditory System

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P2X7 receptor activation downmodulates Na+-dependent high-affinity GABA and glutamate transport into rat brain cortex synaptosomes

Cited by 19 publications

References 66 publications

Up‐regulation of P2X7 receptor–mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex

Up‐regulation of P2X7 receptor–mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex

Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice

Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2in the Auditory System

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Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X₂in the Auditory System