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The effect of high pressure on the NMDA receptor: molecular dynamics simulations.

ABSTRACT: Professional divers exposed to ambient pressures above 11?bar develop the high pressure neurological syndrome (HPNS), manifesting as central nervous system (CNS) hyperexcitability, motor disturbances, sensory impairment, and cognitive deficits. The glutamate-type N-methyl-D-aspartate receptor (NMDAR) has been implicated in the CNS hyperexcitability of HPNS. NMDARs containing different subunits exhibited varying degrees of increased/decreased current at high pressure. The mechanisms underlying this phenomenon remain unclear. We performed 100?ns molecular dynamics (MD) simulations of the NMDAR structure embedded in a dioleoylphosphatidylcholine (DOPC) lipid bilayer solvated in water at 1?bar, hydrostatic 25?bar, and in helium at 25?bar. MD simulations showed that in contrast to hydrostatic pressure, high pressure helium causes substantial distortion of the DOPC membrane due to its accumulation between the two monolayers: reduction of the Sn-1 and Sn-2 DOPC chains and helium-dependent dehydration of the NMDAR pore. Further analysis of important regions of the NMDAR protein such as pore surface (M2 ?-helix), Mg2+ binding site, and TMD-M4 ?-helix revealed significant effects of helium. In contrast with previous models, these and our earlier results suggest that high pressure helium, not hydrostatic pressure per se, alters the receptor tertiary structure via protein-lipid interactions. Helium in divers' breathing mixtures may partially contribute to HPNS symptoms.

SUBMITTER: Bliznyuk A

PROVIDER: S-EPMC6658662 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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The effect of high pressure on the NMDA receptor: molecular dynamics simulations.

Bliznyuk Alice A Grossman Yoram Y Moskovitz Yevgeny Y

Scientific reports 20190725 1

Professional divers exposed to ambient pressures above 11 bar develop the high pressure neurological syndrome (HPNS), manifesting as central nervous system (CNS) hyperexcitability, motor disturbances, sensory impairment, and cognitive deficits. The glutamate-type N-methyl-D-aspartate receptor (NMDAR) has been implicated in the CNS hyperexcitability of HPNS. NMDARs containing different subunits exhibited varying degrees of increased/decreased current at high pressure. The mechanisms underlying th ...[more]

PMID: 31346207

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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: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.

Dataset Information

The effect of high pressure on the NMDA receptor: molecular dynamics simulations.

Publications

The effect of high pressure on the NMDA receptor: molecular dynamics simulations.

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