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Inorganic Polyphosphate Regulates AMPA and NMDA Receptors and Protects Against Glutamate Excitotoxicity via Activation of P2Y Receptors

Maiolino, M; O'Neill, N; Lariccia, V; Amoroso, S; Sylantyev, S; Angelova, PR; Abramov, AY; (2019) Inorganic Polyphosphate Regulates AMPA and NMDA Receptors and Protects Against Glutamate Excitotoxicity via Activation of P2Y Receptors. The Journal of Neuroscience , 39 (31) pp. 6038-6048. 10.1523/JNEUROSCI.0314-19.2019. Green open access

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Abstract

Glutamate is one of the most important neurotransmitters in the process of signal transduction in the central nervous system. Excessive amounts of this neurotransmitter lead to glutamate excitotoxicity which is accountable for neuronal death in acute neurological disorders including stroke, trauma, and in neurodegenerative diseases. Inorganic polyphosphate (PolyP) plays multiple roles in the mammalian brain, including function as a calcium-dependent gliotransmitter mediating communication between astrocytes, while its role in the regulation of neuronal activity is unknown. Here we studied the effect of polyP on glutamate-induced calcium signal in primary rat neurons in both physiological and pathological conditions. We found that pre-incubation of primary neurons with polyP reduced glutamate- and AMPA- but not the NMDA-induced calcium signal. However, in rat hippocampal acute slices polyP reduced ion flux through NMDA and AMPA receptors in native neurons. The effect of polyP on glutamate and specifically on the AMPA receptors was dependent on the presence of P2Y1 but not of P2X receptor inhibitors and also could be mimicked by P2Y1 agonist 2MeSADP. Pre-incubation of cortical neurons with polyP significantly reduced the initial calcium peak as well as the number of neurons with delayed calcium deregulation in response to high concentrations of glutamate and resulted in protection of neurons against glutamate-induced cell death. As a result, activation of P2Y1 receptors by polyP reduced calcium signal acting through AMPA receptors, thus protecting neurons against glutamate excitotoxicity by reduction of the calcium overload and restoration of mitochondrial function.Significance StatementOne of the oldest polymers in the evolution of living matter is the inorganic polyphosphate. It is shown to play a role of gliotransmitter in the brain; however, the role of polyphosphate in neuronal signalling is not clear. Here we demonstrate that inorganic polyphosphate is able to reduce calcium signal, induced by physiological or high concentrations of glutamate. The effect of polyphosphate on glutamate-induced calcium signal in neurons is due to the effect of this polymer on the AMPA receptors.The effect of polyP on glutamate- and AMPA-induced calcium signal is dependent on P2Y receptor antagonist. The ability of polyphosphate to restrict glutamate-induced calcium signal lies in the basis of its protection of neurons against glutamate excitotoxicity.

Type: Article
Title: Inorganic Polyphosphate Regulates AMPA and NMDA Receptors and Protects Against Glutamate Excitotoxicity via Activation of P2Y Receptors
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.0314-19.2019
Publisher version: https://doi.org/10.1523/JNEUROSCI.0314-19.2019
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: inorganic polyphosphate, glutamate excitotoxicity, AMPA, NMDA, calcium signaling
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10075661
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