Mechanism Study Of Ionic Glutamate Receptor-mediated Excitotoxicity

Excitotoxicity induced by overactivation of N-methyl-D-aspartate receptor(NMDAR)is one of the earliest discovered and widely recognized molecular mechanisms of nerve injury in ischemic stroke,and it is theoretically inhibited with NMDAR activity to reduce brain injury.However,studies have shown that due to the complex effect of specific NMDAR subunit antagonists on NMDAR,resulting in inconsistent clinical trial results,the search for new mechanisms to regulate NMDAR activity to develop more stable and effective neuroprotectors remains to be studied.(1)This study found that the expression of the three subunits(GluN2 A,GluN2 B,GluN2C)of NMDAR in the environment of ischemia and glucose increased compared with the normal culture conditions,among which the expression of GluN2 B protein increased significantly,and by comparing the changes of GluN2A/2B/2C protein expression,it was determined that the main participation of the NMDAR subunit in the hypoglycemic and hypoxic environment was GluN2 B.The glycogenic and hypoxic environment prolongs the half-life of GluN2A/2B/2C.The degradation pathway of GluN2A/2B/2C was identified as the ubiquitin-proteasome pathway.Studying the protein expression,half-life changes and degradation pathways of GluN2A/2B/2C subunits of NMDAR after glucose deficiency and hypoxia can provide new ideas for dealing with nerve damage caused by excessive activation of NMDAR after cerebral ischemia.(2)In this paper,the SWISS-MODLE database was used to homologous modeling GluN2A/2B/2C,and the possible potential interactions between coding proteins were retrieved using the STRING database based on the three-dimensional model.We established a high-quality three-dimensional model through homologous modeling,and predicted GluN2A/2B/2C interaction protein based on GluN2A/2B/2C structural model,and obtained an interaction protein network with high confidence.In order to inhibit excitotoxicity,it provides a theoretical basis and a new target for the treatment of cerebral ischemic neuropathy.This study can provide new ideas for the development of new mode of action neuroprotectors around NMDAR activity,and will play a positive role in promoting the development of new treatment strategies for ischemic brain injury,traumatic brain injury and other neurological diseases,and has practical significance for finding specific antagonists to deal with neurotoxic nerve damage.