Extracellular mild acidosis decreases the Ca2+ permeability of the human NMDA receptors

Simona Plutino, Miriam Sciaccaluga, Sergio Fucile

Research output: Contribution to journalArticle

Abstract

NMDA receptors (NMDARs) are glutamate-gated ion channels involved in excitatory synaptic transmission and in others physiological processes such as synaptic plasticity and development. The overload of Ca2+ ions through NMDARs, caused by an excessive activation of receptors, leads to excitotoxic neuronal cell death. For this reason, the reduction of Ca2+ flux through NMDARs has been a central focus in finding therapeutic strategies to prevent neuronal cell damage. Extracellular H+ are allosteric modulators of NMDARs. Starting from previous studies showing that extracellular mild acidosis reduces NMDA-evoked whole cell currents, we analyzed the effects of this condition on the NMDARs Ca2+ permeability, measured as "fractional calcium current" (Pf, i.e. the percentage of the total current carried by Ca2+ ions), of human NMDARs NR1/NR2A and NR1/NR2B transiently transfected in HeLa cells. Extracellular mild acidosis significantly reduces Pf of both human NR1/NR2A and NR1/NR2B NMDARs, also decreasing single channel conductance in outside out patches for NR1/NR2A receptor. Reduction of Ca2+ flux through NMDARs was also confirmed in cortical neurons in culture. A comparative analysis of both NMDA evoked Ca2+ transients and whole cell currents showed that extracellular H+ differentially modulate the permeation of Na+ and Ca2+ through NMDARs. Our data highlight the synergy of two distinct neuroprotective mechanisms during acidosis: Ca2+ entry through NMDARs is lowered due to the modulation of both open probability and Ca2+ permeability. Furthermore, this study provides the proof of concept that it is possible to reduce Ca2+ overload in neurons modulating the NMDAR Ca2+ permeability.

Original languageEnglish
Pages (from-to)63-70
Number of pages8
JournalCell Calcium
Volume80
DOIs
Publication statusPublished - Jun 2019

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Acidosis
N-Methyl-D-Aspartate Receptors
Permeability
N-Methylaspartate
Ions
Physiological Phenomena
Neurons
Neuronal Plasticity
Ion Channels
HeLa Cells
Synaptic Transmission
Glutamic Acid
Cell Death
Calcium

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Extracellular mild acidosis decreases the Ca2+ permeability of the human NMDA receptors. / Plutino, Simona; Sciaccaluga, Miriam; Fucile, Sergio.

In: Cell Calcium, Vol. 80, 06.2019, p. 63-70.

Research output: Contribution to journalArticle

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AU - Fucile, Sergio

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N2 - NMDA receptors (NMDARs) are glutamate-gated ion channels involved in excitatory synaptic transmission and in others physiological processes such as synaptic plasticity and development. The overload of Ca2+ ions through NMDARs, caused by an excessive activation of receptors, leads to excitotoxic neuronal cell death. For this reason, the reduction of Ca2+ flux through NMDARs has been a central focus in finding therapeutic strategies to prevent neuronal cell damage. Extracellular H+ are allosteric modulators of NMDARs. Starting from previous studies showing that extracellular mild acidosis reduces NMDA-evoked whole cell currents, we analyzed the effects of this condition on the NMDARs Ca2+ permeability, measured as "fractional calcium current" (Pf, i.e. the percentage of the total current carried by Ca2+ ions), of human NMDARs NR1/NR2A and NR1/NR2B transiently transfected in HeLa cells. Extracellular mild acidosis significantly reduces Pf of both human NR1/NR2A and NR1/NR2B NMDARs, also decreasing single channel conductance in outside out patches for NR1/NR2A receptor. Reduction of Ca2+ flux through NMDARs was also confirmed in cortical neurons in culture. A comparative analysis of both NMDA evoked Ca2+ transients and whole cell currents showed that extracellular H+ differentially modulate the permeation of Na+ and Ca2+ through NMDARs. Our data highlight the synergy of two distinct neuroprotective mechanisms during acidosis: Ca2+ entry through NMDARs is lowered due to the modulation of both open probability and Ca2+ permeability. Furthermore, this study provides the proof of concept that it is possible to reduce Ca2+ overload in neurons modulating the NMDAR Ca2+ permeability.

AB - NMDA receptors (NMDARs) are glutamate-gated ion channels involved in excitatory synaptic transmission and in others physiological processes such as synaptic plasticity and development. The overload of Ca2+ ions through NMDARs, caused by an excessive activation of receptors, leads to excitotoxic neuronal cell death. For this reason, the reduction of Ca2+ flux through NMDARs has been a central focus in finding therapeutic strategies to prevent neuronal cell damage. Extracellular H+ are allosteric modulators of NMDARs. Starting from previous studies showing that extracellular mild acidosis reduces NMDA-evoked whole cell currents, we analyzed the effects of this condition on the NMDARs Ca2+ permeability, measured as "fractional calcium current" (Pf, i.e. the percentage of the total current carried by Ca2+ ions), of human NMDARs NR1/NR2A and NR1/NR2B transiently transfected in HeLa cells. Extracellular mild acidosis significantly reduces Pf of both human NR1/NR2A and NR1/NR2B NMDARs, also decreasing single channel conductance in outside out patches for NR1/NR2A receptor. Reduction of Ca2+ flux through NMDARs was also confirmed in cortical neurons in culture. A comparative analysis of both NMDA evoked Ca2+ transients and whole cell currents showed that extracellular H+ differentially modulate the permeation of Na+ and Ca2+ through NMDARs. Our data highlight the synergy of two distinct neuroprotective mechanisms during acidosis: Ca2+ entry through NMDARs is lowered due to the modulation of both open probability and Ca2+ permeability. Furthermore, this study provides the proof of concept that it is possible to reduce Ca2+ overload in neurons modulating the NMDAR Ca2+ permeability.

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