Role of NMDA Receptor in High-Pressure Neurological Syndrome and Hyperbaric Oxygen Toxicity

Abstract

Professional divers exposed to pressures greater than 11 ATA (1.1 MPa) may suffer from high-pressure neurological syndrome (HPNS). Divers who use closed-circuit breathing apparatus and patients and medical attendants undergoing hyperbaric oxygen therapy (HBOT) face the risk of CNS hyperbaric oxygen toxicity (HBOTx) at oxygen pressure above 2 ATA (0.2 MPa). Both syndromes are characterized by reversible CNS hyperexcitability, accompanied by cognitive and motor deficits, and N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in provoking them. Various NMDAR subtypes respond differently under hyperbaric conditions. The augmented currents observed only in NMDAR containing GluN2A subunit increase glutamatergic synaptic activity and cause dendritic hyperexcitability and abnormal neuronal activity. Removal of the resting Zn²⁺ voltage-independent inhibition exerted by GluN2A present in the NMDAR is the major candidate for the mechanism underlying the increase in receptor conductance. Therefore, this process should be the main target for future research aiming at developing neuroprotection against HPNS and HBOTx.

Keywords: GluN2A; HBOTx; HPNS; NMDAR; Zn2+ voltage-independent inhibition; high pressure.

Figure 1

(A) Simulated NMDAR embedded in a DOPC lipid bilayer at 1 ATA pressure. The NMDAR is shown as a cartoon colored with chains of the four subunits (green, magenta, yellow, cyan), DOPC is presented as spheres in wheat and red color (colored by element), (B) One subunit of the NMDAR in the membrane, important sites indicated with a red circle. All GluN subunits share a modular architecture that is composed of four distinct domains: the N-terminal domain (NTD), the agonist-binding domain (ABD) that binds glycine or d-serine in GluN1 and GluN3 and glutamate in GluN2, the transmembrane domain (TMD) containing the ion channel, and an intracellular C-terminal domain (CTD) (not shown in the figure). The NTD and CTD are the most divergent regions. (C) Schematic topology of the NMDAR and its subunits (D) NMDAR asparagine (Asn) residues coordinations at the Mg²⁺ site. Asn residues are shown as sticks colored by element on the M2 region of the TMD of the four subunits.