RESUMEN
N-methyl-D-aspartate (NMDA) receptors are heterotetrametric ion channels composed of two obligatory GluN1 subunits and two alternative GluN2 or GluN3 subunits, forming GluN1-N2, GluN1-N3, and GluN1-N2-N3 type of NMDA receptors. Extensive research has focused on the functional and structural properties of conventional GluN1-GluN2 NMDA receptors due to their early discovery and high expression levels. However, the knowledge of unconventional GluN1-N3 NMDA receptors remains limited. In this study, we modeled the GluN1-N3A, GluN1-N3B, and GluN1-N3A-N3B NMDA receptors using deep-learned protein-language predication algorithms AlphaFold and RoseTTAFold All-Atom. We then compared these structures with GluN1-N2 and GluN1-N3A receptor cryo-EM structures and found that GluN1-N3 receptors have distinct properties in subunit arrangement, domain swap, and domain interaction. Furthermore, we predicted the agonist- or antagonist-bound structures, highlighting the key molecular-residue interactions. Our findings shed new light on the structural and functional diversity of NMDA receptors and provide a new direction for drug development. This study uses advanced AI algorithms to model GluN1-N3 NMDA receptors, revealing unique structural properties and interactions compared to conventional GluN1-N2 receptors. By highlighting key molecular-residue interactions and predicting ligand-bound structures, our research enhances the understanding of NMDA receptor diversity and offers new insights for targeted drug development.
RESUMEN
Mongolian gerbils (Meriones unguiculatus) show a wide thermal neutral zone (TNZ, 26.5-38.9⯰C). Whether heat shock proteins (HSPs) are involved in thermal tolerance for gerbils has still been unknown. We investigated the effects of acute and chronic high temperature within and above TNZ on the expressions of HSP70 and HSP90 and oxidative status in Mongolian gerbils, to test the hypothesis that the gerbils need increase the expression in HSPs to defense the acute and chronic heat stress. In experiment I, 50 Mongolian gerbils were exposed to 23⯰C, 27⯰C, 37⯰C, 40⯰C and 43.5⯰C for 80â¯min respectively, and then sacrificed 12â¯h after treatment. HSP70 expression in the liver increased at 40⯰C compared to that at 23⯰C, but did not change after 27⯰C, 37⯰C or 43.5⯰C exposure. There were no differences in HSP90 expression, oxidative stress parameters such as malonaldehyde (MDA) and hydrogen peroxide (H2O2), or antioxidant parameters such as superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) in the liver. HSP70 and HSP90 expression both in the heart and brain showed no differences among groups. In experiment II, another set of 30 gerbils were acclimated to 23⯰C, 27⯰C and 37⯰C for 21 days, respectively. During chronic acclimation, HSP70 expression increased and H2O2 level decreased in the liver in 37⯰C group compared to other two groups. Both H2O2 and SOD in the brain decreased in 37⯰C group, but there were no differences in HSP70, MDA or T-AOC in the brain. These data indicate that Mongolian gerbils can maintain basal levels of HSPs after acute exposure to temperatures within the wide TNZ, but rely on increased HSP70 in the liver to protect from heat damage at temperatures above TNZ and during chronic heat acclimation. The increased HSP70 expression in the liver may contribute to keeping from heat damage in desert rodents.