Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors

Xie, Mian; Leng, Tiandong; Maysami, Samaneh; Pearson, Andrea; Simon, Roger; Xiong, Zhi-Gang; Meller, Robert

Abstract

In this study, we characterize biophysical changes in NMDA receptor function in response to brief non-injurious ischemic stress (ischemic preconditioning). Electrophysiological studies show NMDA receptor function is reduced following preconditioning in cultured rat cortical neurons. This functional change is not due to changes in the reversal potential of the receptor, but an increase in desensitization. We performed concentration–response analysis of NMDA-evoked currents, and demonstrate that preconditioned neurons show a reduced potency of NMDA to evoke currents, an increase in Mg2+ sensitivity, but no change in glycine sensitivity. Antagonists studies show a reduced inhibition of GluN2B antagonists that have an allosteric mode of action (ifenprodil and R-25-6981), but competitive antagonists at the GluR2A and 2B receptor (NVP-AMM077 and conantokin-G) appear to have similar potency to block currents. Biochemical studies show a reduction in membrane surface GluN2B subunits, and an increased co-immunoprecipitation of GluN2A with GluN2B subunits, suggestive of tri-heteromeric receptor formation. Finally, we show that blocking actin remodeling with jasplakinolide, a mechanism of rapid ischemic tolerance, prevents NMDA receptor functional changes and co-immunoprecipitation of GluN2A and 2B subunits. Together, this study shows that alterations in NMDA receptor function following preconditioning ischemia are associated with neuroprotection in rapid ischemic tolerance.

Citation

Xie, M., Leng, T., Maysami, S., Pearson, A., Simon, R., Xiong, Z.-G., & Meller, R. (2022). Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors. Biomolecules, 12(9), Article 1214. https://doi.org/10.3390/biom12091214

• Journal Article Type: Article
• Acceptance Date: Aug 26, 2022
• Online Publication Date: Sep 1, 2022
• Publication Date: Sep 1, 2022
• Journal: Biomolecules
• Publisher: MDPI
• Volume: 12
• Issue: 9
• Article Number: 1214
• DOI: https://doi.org/10.3390/biom12091214
• Public URL: https://keele-repository.worktribe.com/output/424157
• Publisher URL: https://www.mdpi.com/2218-273X/12/9/1214