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 α-helix), Mg2+ binding site, and TMD-M4 α-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.
Highlights
To provide background information regarding the underlying biological mechanisms of high pressure physiology, we feel it necessary to reiterate the main concepts and experimental findings described in our previous studies[1,2,3]
We propose a new theoretical approach to examine the hypothesis that protein conformational changes, induced directly by high pressure or indirectly via protein-lipid interactions, are responsible for the N-methyl-D-aspartate receptor (NMDAR) hyperexcitability induced by elevated pressure
It is important to note that the percolation time of neon into the DOPC bi-layer was determined to be in the range of 5‒10 ns, and is positively correlated with high pressure
Summary
To provide background information regarding the underlying biological mechanisms of high pressure physiology, we feel it necessary to reiterate the main concepts and experimental findings described in our previous studies[1,2,3]. NMDARs are responsible for mediating excitatory synaptic transmission within the CNS15 They belong to the family of ionotropic glutamate receptors and have 14 different structural subunits. The GluN1 family is encoded by one gene and may present eight different subunits due to alternative RNA splicing mechanisms[16]: GluN1-1a www.nature.com/scientificreports/. Previous electrophysiological studies of rat brain slices in high pressure helium showed a significant increase in the synaptic NMDAR response followed by postsynaptic excitability changes[27,28] and reduced efficiency of Mg2+ blockade[28]. Recent molecular studies conducted in our laboratory[1,2,29] have revealed that different subunit combinations of the NMDAR exhibit different, sometimes antagonistic, current amplitude change under high pressure helium, whereas receptors containing GluN1-4a or GluN1-4b splice variants were observed to mediate dichotomic current responses[2]
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