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Front Physiol
2020 Jan 01;11:1057. doi: 10.3389/fphys.2020.01057.
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The Mechanism of NMDA Receptor Hyperexcitation in High Pressure Helium and Hyperbaric Oxygen.
Bliznyuk A
,
Hollmann M
,
Grossman Y
.
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Professional divers exposed to pressures greater than 1.1 MPa may suffer from the high pressure neurological syndrome (HPNS). Divers who use closed-circuit breathing apparatus face the risk of CNS hyperbaric oxygen toxicity (HBOTox). Both syndromes are characterized by reversible CNS hyperexcitability, accompanied by cognitive and motor deficits. Previous studies have demonstrated that the hyperexcitability of HPNS is induced mainly by NMDA receptors (NMDARs). In our recent studies, we demonstrated that the response of NMDARs containing GluN1 + GluN2A subunits was increased by up to 50% at high pressure (HP) He, whereas GluN1 + GluN2B NMDARs response was not affected under similar conditions. Our aim was to compare the responses of both types of NMDARs under HBOTox conditions to those of HP He and to reveal their possible underlying molecular mechanism(s). The two combinations of NMDARs were expressed in Xenopus laevis oocytes, placed in a pressure chamber, voltage-clamped, and their currents were tested at 0.1 (control) -0.54 MPa 100% O2 or 0.1-5.1 MPa He pressures. We show, for the first time, that NMDARs containing the GluN2A subunit exhibit increased responses in 100% O2 at a pressure of 0.54 MPa, similar to those observed in 5.1 MPa He. In contrast, the GluN1 + GluN2B response is not sensitive to either condition. We discovered that neither condition produced statistically significant changes in the voltage-dependent Mg2+ inhibition of the response. The averaged IC50 remained the same, but a higher [Mg2+]
o
was required to restore the current to its control value. The application of TPEN, a Zn2+ chelator, in control, HP He and HBOTox conditions, revealed that the increase in GluN1 + GluN2A current is associated with the removal of the high-affinity voltage-independent Zn2+ inhibition of the receptor. We propose that HPNS and HBOTox may share a common mechanism, namely removal of Zn2+ from its specific binding site on the N-terminal domain of the GluN2A subunit, which increases the pore input-conductance and produces larger currents and consequently a hyperexcitation.
FIGURE 1. Current amplitudes of the GluN1-1a + GluN2A subtype in HBO at different pressures. (A) An example of HBO effects on GluN1-1a + GluN2A current response. All pressure steps were applied to the same oocyte. The applied agonists were glutamate (100 μM) and glycine (10 μM) with no [Mg2+]o added. The 20 s agonists application time is indicated by horizontal bars. (B) Quantitative analysis of the NMDAR currents. Responses were normalized to the control value at 0.1 MPa (when the recording solution is saturated with 100% O2) for each tested oocyte (indicated by numbers in the bars). Oocytes were exposed to 2–4 increased pressure steps. ∗∗p < 0.01.
FIGURE 2. Current amplitudes of the GluN1-1a + GluN2A subtype at different [Mg2+]o. Currents were normalized (%) to the [Mg2+]o = 0 response at 0.1 MPa. (A) Compression with He (n = 8). (B) Compression with 100% O2 (n = 11).
FIGURE 3. Example of the HP He effect on the Mg2+ dose-response curve. There were no significant changes in the dose-response curve and the IC50 for the GluN1-1a + GluN2A subtype (measurements were performed on the same oocyte under control and HP He conditions). Current amplitudes of the receptor were normalized to its [Mg2+]o = 0 response, and dose-response curve fit was performed for each experiment.
FIGURE 4. Quantitative analysis of GluN1-1a + GluN2A current changes in HP He and HBO with and without TPEN. Current amplitude is expressed as mean ± SEM in control (0.1 MPa), 0.54 MPa O2 and 5.1 MPa He, with 0 μM or 1 μM TPEN. Splice variant GluN1-1a was co-expressed with the GluN2A subunit. Numbers in the bars indicate number of oocytes tested. **p < 0.005, ***p < 0.001.
FIGURE 5. Quantitative analysis of GluN1-1a + GluN2B currents in HBO and with TPEN. (A) Current amplitude expressed as mean ± SEM in control (0.1 MPa) and 0.54 MPa O2 (n = 7). (B) Current amplitude expressed as mean ± SEM with 0 μM or 1 μM TPEN in control (0.1 MPa) (n = 5). No statistically significant difference was found for either experiment.
Aviner,
Selective modulation of cellular voltage-dependent calcium channels by hyperbaric pressure-a suggested HPNS partial mechanism.
2014, Pubmed,
Xenbase
Aviner,
Selective modulation of cellular voltage-dependent calcium channels by hyperbaric pressure-a suggested HPNS partial mechanism.
2014,
Pubmed
,
Xenbase
Bliznyuk,
The effect of high pressure on the NMDA receptor: molecular dynamics simulations.
2019,
Pubmed
Bliznyuk,
The Enigma of the Dichotomic Pressure Response of GluN1-4a/b Splice Variants of NMDA Receptor: Experimental and Statistical Analyses.
2016,
Pubmed
,
Xenbase
Bliznyuk,
High Pressure Stress Response: Involvement of NMDA Receptor Subtypes and Molecular Markers.
2019,
Pubmed
Bliznyuk,
The N-methyl-D-aspartate receptor's neglected subunit - GluN1 matters under normal and hyperbaric conditions.
2015,
Pubmed
,
Xenbase
Butler,
Central nervous system oxygen toxicity in closed circuit scuba divers II.
1986,
Pubmed
Dean,
Neuronal sensitivity to hyperoxia, hypercapnia, and inert gases at hyperbaric pressures.
2003,
Pubmed
Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed
Fagni,
Helium pressure potentiates the N-methyl-D-aspartate- and D,L-homocysteate-induced decreases of field potentials in the rat hippocampal slice preparation.
1987,
Pubmed
Fagni,
A study of spontaneous and evoked activity in the rat hippocampus under helium-oxygen high pressure.
1985,
Pubmed
Grossman,
Pressure and temperature: time-dependent modulation of membrane properties in a bifurcating axon.
1984,
Pubmed
Halsey,
Effects of high pressure on the central nervous system.
1982,
Pubmed
Ishihara,
Mild hyperbaric oxygen: mechanisms and effects.
2019,
Pubmed
Katz,
Magnesium sulfate suppresses electroencephalographic manifestations of CNS oxygen toxicity.
1990,
Pubmed
Mor,
Pressure-selective modulation of NMDA receptor subtypes may reflect 3D structural differences.
2012,
Pubmed
,
Xenbase
Mor,
High pressure modulation of NMDA receptor dependent excitability.
2007,
Pubmed
Mor,
The efficacy of physiological and pharmacological N-methyl-D-aspartate receptor block is greatly reduced under hyperbaric conditions.
2010,
Pubmed
Mor,
Modulation of isolated N-methyl-d-aspartate receptor response under hyperbaric conditions.
2006,
Pubmed
Paoletti,
High-affinity zinc inhibition of NMDA NR1-NR2A receptors.
1997,
Pubmed
,
Xenbase
Paoletti,
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.
2013,
Pubmed
Pearce,
Protection from high pressure induced hyperexcitability by the AMPA/kainate receptor antagonists GYKI 52466 and LY 293558.
1994,
Pubmed
Roberts,
Glycine activation of human homomeric alpha 1 glycine receptors is sensitive to pressure in the range of the high pressure nervous syndrome.
1996,
Pubmed
,
Xenbase
Romero-Hernandez,
Molecular Basis for Subtype Specificity and High-Affinity Zinc Inhibition in the GluN1-GluN2A NMDA Receptor Amino-Terminal Domain.
2016,
Pubmed
,
Xenbase
Shelton,
The effect of high pressure on glycine- and kainate-sensitive receptor channels expressed in Xenopus oocytes.
1993,
Pubmed
,
Xenbase
Tibbles,
Hyperbaric-oxygen therapy.
1996,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Tu,
The differential contribution of GluN1 and GluN2 to the gating operation of the NMDA receptor channel.
2015,
Pubmed
Wollmuth,
Adjacent asparagines in the NR2-subunit of the NMDA receptor channel control the voltage-dependent block by extracellular Mg2+.
1998,
Pubmed
,
Xenbase
Zinebi,
Excitatory and inhibitory amino-acidergic determinants of the pressure-induced neuronal hyperexcitability in rat hippocampal slices.
1990,
Pubmed
Zinebi,
Decrease of recurrent and feed-forward inhibitions under high pressure of helium in rat hippocampal slices.
1988,
Pubmed