Pressure-selective modulation of NMDA receptor subtypes may reflect 3D structural differences

Abstract

Professional deep-water divers exposed to high pressure (HP) above 1.1 MPa suffer from High Pressure Neurological Syndrome (HPNS), which is associated with CNS hyperexcitability. We have previously reported that HP augments N-methyl-D-aspartate receptor (NMDAR) synaptic responses, increases neuronal excitability, and potentially causes irreversible neuronal damage. We now report that HP (10.1 MPa) differentially affects eight specific NMDAR subtypes. GluN1(1a or 1b) was co-expressed with one of the four GluN2(A–D) subunits in Xenopus laevis oocytes. HP increased ionic currents (measured by two electrode voltage clamps) of one subtype, reduced the current in four others, and did not affect the current in the remaining three. 3D theoretical modeling was aimed at revealing specific receptor domains involved with HP selectivity. In light of the information on the CNS spatial distribution of the different NMDAR subtypes, we conclude that the NMDAR's diverse responses to HP may lead to selective HP effects on different brain regions. These discoveries call for further and more specific investigation of deleterious HP effects and suggest the need for a re-evaluation of deep-diving safety guidelines.

Selective modulation of cellular voltage-dependent calcium channels by hyperbaric pressure—a suggested HPNS partial mechanism

“…Preliminary results from experiments on the NMDA receptor at HP may suggest that even changes in the extracellular N terminal domain can influence the magnitude and direction of the pressure effect (Mor et al, 2012). …”

The N‐methyl‐D‐aspartate receptor's neglected subunit – GluN1 matters under normal and hyperbaric conditions

“…The solutions were introduced into the pressure chamber by means of a high‐pressure pump (‘minipump’, LDC Analytical Inc., Riviera Beach, FL, USA). Unlike our previous studies (Mor et al ., , ), in the present study [Ca 2+ ] o was substituted for by [Ba 2+ ] o in the physiological solution in order to avoid Ca 2+ ‐induced transient chloride currents, channel subconductance, and divalent cation‐induced current inactivation [see Mor et al . () for details].…”

“…Unlike our previous studies (Mor et al ., , ), in the present study [Ca 2+ ] o was substituted for by [Ba 2+ ] o in the physiological solution in order to avoid Ca 2+ ‐induced transient chloride currents, channel subconductance, and divalent cation‐induced current inactivation [see Mor et al . () for details]. In order to validate the [Ca 2+ ] o substitution by [Ba 2+ ] o , we exposed the same oocytes to Ca 2+ solution and after that to Ba 2+ solution at control and HPs (Table , Fig.…”

“…Recently, our laboratory has reported (Mor et al ., ) differential current responses under HP conditions in NMDAR subtypes that contain either GluN1‐1a or GluN1‐1b splice variants co‐expressed in oocytes with all four GluN2 subunits. We postulated that the GluN1 subunit may also have an important role in characterising the receptor properties.…”

The role of ontogeny in physiological tolerance: decreasing hydrostatic pressure tolerance with development in the northern stone crabLithodes maja

“…N-methyl-D-aspartate (NMDA) receptors are thought to play an important role in the onset of high-pressure neurological syndrome (HPNS) in vertebrates, which is characterized by a series of consistent pathologies, including convulsions [42][43][44]. HPNS occurs as a result of hyper-excitability of the central nervous system, and studies in rats and the frog Xenopus laevis support the hypothesis that it is characterized in part by an increase in the sensitivity of the NMDA receptor [45,46]. By quantifying expression of these genes, we are able to examine the molecular physiological constraints acting on the early life stages of L. maja, and the degree to which acute changes in hydrostatic pressure might constrain bathymetric distributions at each ontogenetic stage.…”