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The Mechanism of NMDA Receptor Hyperexcitation in High Pressure Helium and Hyperbaric Oxygen.

ABSTRACT: 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.

SUBMITTER: Bliznyuk A

PROVIDER: S-EPMC7478267 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Mechanism of NMDA Receptor Hyperexcitation in High Pressure Helium and Hyperbaric Oxygen.

Bliznyuk Alice A Hollmann Michael M Grossman Yoram Y

Frontiers in physiology 20200825

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 demonstra ...[more]

PMID: 32982789

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Project description:Divers that are exposed to high pressure (HP) above 1.1 MPa suffer from High Pressure Neurological Syndrome (HPNS), which is implicated with central nervous system (CNS) malfunction. Marine mammals performing extended and deep breath-hold dives are exposed to almost 20 MPa without apparent HPNS symptoms. N-methyl-D-aspartate receptor (NMDAR) has repeatedly been implicated as one of the major factors in CNS hyperexcitability as part of HPNS. Electrophysiological studies in rat brain slices at He HP showed a significant increase in the synaptic NMDAR response, followed by postsynaptic excitability changes. Molecular studies of Rattus norvegicus NMDARs have revealed that different subunit combinations of the NMDAR exhibit different, increased or decreased, current responses under He HP conditions. The purpose of the present research was to disclose if the breath-hold deep diving mammals exhibit NMDAR structural modifications related to HP. We used sequence alignment and homology structure modeling in order to compare deep diving marine mammals' NMDARs to those of terrestrial mammals. We discovered that deep diving mammals have a special tertiary TMD structure of the GluN2A subunit that differs from that of the terrestrial mammals. In addition, the GluN2A subunit has a group of four conserved a.a. substitutions: V68L (N-terminal domain, NTD) and V440I (agonist-binding domain, ABD) are cetacean specific, E308D (N-terminal domain, NTD) and I816V (transmembrane domain, TMD) were also singularly found in some terrestrial mammals. Since I816V is localized in M4 ?-helix region, which is critical for NMDAR activation and desensitization, we hypothesize that the presence of all 4 substitutions rather than a single one, is the combination that may enable HP tolerance. Furthermore, additional special substitutions that were found in the marine mammals' NTD may affect the Zn2+ binding site, suggesting less or no voltage-independent inhibition by this ion. Our molecular studies of NMDARs containing the GluN2A subunit showed that HP removal of the Zn2+ voltage-independent inhibition could be the mechanism explaining its current increase at HP. Thus, this mechanism could play a crucial role in the CNS hyperexcitability at HP. Less or no voltage-independent Zn2+ inhibition, different conformations of the TMD, and special mutation in the M4 ?-helix region of cetaceans' NMDAR, may give them the advantage they need in order to perform such deep dives without CNS malfunction.

Project description:Hyperbaric Oxygen (HBO2) has been proposed as a pre-conditioning method to enhance exercise performance. Most prior studies testing this effect have been limited by inadequate methodologies. Its potential efficacy and mechanism of action remain unknown. We hypothesized that HBO2 could enhance aerobic capacity by inducing mitochondrial biogenesis via redox signaling in skeletal muscle. HBO2 was administered in combination with high-intensity interval training (HIIT), a potent redox stimulus known to induce mitochondrial biogenesis. Aerobic capacity was tested during acute hypobaric hypoxia seeking to shift the limiting site of whole body V̇O2 from convection to diffusion, more closely isolating any effect of improved oxidative capacity. Healthy volunteers were screened with sea-level (SL) V̇O2peak testing. Seventeen subjects were enrolled (10 men, 7 women, ages 26.5±1.3 years, BMI 24.6±0.6 kg m-2, V̇O2peak SL = 43.4±2.1). Each completed 6 HIIT sessions over 2 weeks randomized to breathing normobaric air, "HIIT+Air" (PiO2 = 0.21 ATM) or HBO2 (PiO2 = 1.4 ATM) during training, "HIIT+HBO2" group. Training workloads were individualized based on V̇O2peak SL test. Vastus Lateralis (VL) muscle biopsies were performed before and after HIIT in both groups. Baseline and post-training V̇O2peak tests were conducted in a hypobaric chamber at PiO2 = 0.12 ATM. HIIT significantly increased V̇O2peak in both groups: HIIT+HBO2 31.4±1.5 to 35.2±1.2 ml kg-1·min-1 and HIIT+Air 29.0±3.1 to 33.2±2.5 ml kg-1·min-1 (p = 0.005) without an additional effect of HBO2 (p = 0.9 for interaction of HIIT x HBO2). Subjects randomized to HIIT+HBO2 displayed higher skeletal muscle mRNA levels of PPARGC1A, a regulator of mitochondrial biogenesis, and HK2 and SLC2A4, regulators of glucose utilization and storage. All other tested markers of mitochondrial biogenesis showed no additional effect of HBO2 to HIIT. When combined with HIIT, short-term modest HBO2 (1.4 ATA) has does not increase whole-body V̇O2peak during acute hypobaric hypoxia. (ClinicalTrials.gov Identifier: NCT02356900; https://clinicaltrials.gov/ct2/show/NCT02356900).

Dataset Information

The Mechanism of NMDA Receptor Hyperexcitation in High Pressure Helium and Hyperbaric Oxygen.

Publications

The Mechanism of NMDA Receptor Hyperexcitation in High Pressure Helium and Hyperbaric Oxygen.

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