The effect of high pressure on the NMDA receptor: molecular dynamics simulations OPEN (original) (raw)

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), Mg 2+ 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. 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 1-3. Military and occupational divers who engage in deep diving reach depths greater than 50 m sea water, and are thus exposed to pressures above 6 atmospheres absolute (ATA) or 6 bar, where 1 bar ≅ 10 m sea water. Professional divers in the oil industry perform underwater construction work at an average depth of 200 m. In 1988, professional divers employed by the Comex diving company in the Mediterranean Sea performed the deepest known working dive at a depth of 534 m (53.7 bar) 4. The deepest known test dive in a dry pressure chamber, to a depth of 701 m (70.5 bar) was carried out at the Comex facility in France in 1992 5. To avoid oxygen toxicity and nitrogen narcosis, deep divers use a breathing gas mixture known as trimix, which contains varying percentages of oxygen, nitrogen and helium. Pressures as high as these present the divers' lungs, viscera, and particularly the nervous system, with a considerable physiological challenge. Diving deeper than 11 bar may result in the high pressure neurological syndrome (HPNS) 6 , which is characterized by cognitive and motor deficits and reversible central nervous system (CNS) hyperexcitability. As observed in humans and in animal models, susceptibility to HPNS depends on the compression rate and the absolute ambient pressure at the maximal maintained depth. The majority of signs and symptoms in HPNS have their origin in disturbances of CNS synaptic activity 7. Apart from the symptoms which appear during a dive and are usually reversible, professional divers who engage in repetitive deep sea operations over a period of years may also develop permanent memory and motor impairment 8. In recent years, the activity of N-methyl-D-aspartate receptors (NMDARs) has been discovered as one of the main underlying mechanisms of CNS hyperexcitability at hight pressure and the symptoms of HPNS 9-14. NMDARs are responsible for mediating excitatory synaptic transmission within the CNS 15. 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 1 israel naval Medical institute, Haifa, israel.

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