N-methyl-D-aspartate glutamate receptors(NMDARs)play crucial roles in the pathogenesis of neuronal injuries following a stroke insult;therefore,a plethora of preclinical studies focus on better understanding functions...N-methyl-D-aspartate glutamate receptors(NMDARs)play crucial roles in the pathogenesis of neuronal injuries following a stroke insult;therefore,a plethora of preclinical studies focus on better understanding functions of NMDARs and their associated signaling pathways.Over the past decades,NMDARs have been found to exert dual effects in neuronal deaths signaling and neuronal survival signaling during cerebral ischemia.Moreover,many complex intracellular signaling pathways downstream of NMDAR activation have been elucidated,which provide novel targets for developing much-needed neuro-protectants for patients with stroke.In this review,we will discuss the recent progress in understanding the underlying mechanisms of stroke related to NMDAR activation and the potential therapeutic strategies based on these discoveries.展开更多
The transcription and translation of the immediate-early genes(IEGs),such as Arc,Zif268,eFos and Npas4,are considered to be molecular mechanisms underlying learning and memory.Recent studies have shown that applicatio...The transcription and translation of the immediate-early genes(IEGs),such as Arc,Zif268,eFos and Npas4,are considered to be molecular mechanisms underlying learning and memory.Recent studies have shown that application of NADH triggered the expression of Arc and Zif268 by activation of NMDA receptor(NMDAR)signaling.In this regard,we hypothesize that levels of Npas4 and c Fos,could be modulated by NMDAR activity-dependent NADH.To test our hypothesis,in primary cultured hippocampal neurons,we employed NADH to examine the effects of NADH on IEGs.Further more,NMDARs blocker MK801 were used to investigated the role of NMDAR in NADH's effects.The data of real-time PCR revealed that application of NADH promoted the transcription of Arc,cFos and Npas4.Similarly,Western blot analyses showed that the levels of Arc,c Fos and Npas4 were increased significantly after NADH treatment.展开更多
Excitatory-inhibitory(E/I)balance is essential for normal neural development,behavior and cognition.E/I imbalance leads to a variety of neurological disorders,such as autism and schizophrenia.NMDA receptors(NMDARs)reg...Excitatory-inhibitory(E/I)balance is essential for normal neural development,behavior and cognition.E/I imbalance leads to a variety of neurological disorders,such as autism and schizophrenia.NMDA receptors(NMDARs)regulate AMPAR-mediated excitatory and GABAAR-mediated inhibitory synaptic transmission,suggesting that NMDARs play an important role in the establishment and maintenance of the E/I balance.In this review,we briefly introduced NMDARs,AMPARs and GABAARs,summarized the current studies on E/I balance mediated by NMDARs,and discussed the current advances in NMDAR-mediated AMPAR and GABAAR development.Specifically,we analyzed the role of NMDAR subunits in the establishment and maintenance of E/I balance,which may provide new therapeutic strategies for the recovery of E/I imbalance in neurological disorders.展开更多
In the presence of glutamate and co-agonists, e.g., glycine, the N-methyl-D-aspartate receptor （NMDAR） plays an important role in physiological and pathophysiological brain processes. Previous studies indicate glyci...In the presence of glutamate and co-agonists, e.g., glycine, the N-methyl-D-aspartate receptor （NMDAR） plays an important role in physiological and pathophysiological brain processes. Previous studies indicate glycine could inhibit NMDAR respons- es induced by high concentration of NMDA in hippocampal neurons. The mechanism underlying this inhibitory impact, how- ever, has been unclear. In this study, the whole-cell patch-clamp recording and Ca2＋ imaging with Fluo-3/AM under laser scanning confocal microscope were used to analyze the possible involvement of NMDAR subnnits in this effect. We found that the peak current of NMDARs and Ca2＋ influx induced by high concentration of NMDA were reduced by treatment of gly- cine （0.03-10 I.tmol L-1） in a dose-dependent manner, and that the glycine-dependent inhibition of NMDAR responses, which were induced at 300 mol L-1 NMDA, was reversed by ZnCI2 through the blocking of the NR2A subunit of NMDARs, but was less influenced by ifenprodil, a NR2B inhibitor. Our results suggest that the glycine-dependent inactivation of NMDARs is potentially modulated by the regulatory subunit NR2A.展开更多
文摘N-methyl-D-aspartate glutamate receptors(NMDARs)play crucial roles in the pathogenesis of neuronal injuries following a stroke insult;therefore,a plethora of preclinical studies focus on better understanding functions of NMDARs and their associated signaling pathways.Over the past decades,NMDARs have been found to exert dual effects in neuronal deaths signaling and neuronal survival signaling during cerebral ischemia.Moreover,many complex intracellular signaling pathways downstream of NMDAR activation have been elucidated,which provide novel targets for developing much-needed neuro-protectants for patients with stroke.In this review,we will discuss the recent progress in understanding the underlying mechanisms of stroke related to NMDAR activation and the potential therapeutic strategies based on these discoveries.
文摘The transcription and translation of the immediate-early genes(IEGs),such as Arc,Zif268,eFos and Npas4,are considered to be molecular mechanisms underlying learning and memory.Recent studies have shown that application of NADH triggered the expression of Arc and Zif268 by activation of NMDA receptor(NMDAR)signaling.In this regard,we hypothesize that levels of Npas4 and c Fos,could be modulated by NMDAR activity-dependent NADH.To test our hypothesis,in primary cultured hippocampal neurons,we employed NADH to examine the effects of NADH on IEGs.Further more,NMDARs blocker MK801 were used to investigated the role of NMDAR in NADH's effects.The data of real-time PCR revealed that application of NADH promoted the transcription of Arc,cFos and Npas4.Similarly,Western blot analyses showed that the levels of Arc,c Fos and Npas4 were increased significantly after NADH treatment.
基金the National Natural Science Foundation of China(Grant No.32170975)Guangdong Nature Science Foundation(Grant No.2019A1515011309).
文摘Excitatory-inhibitory(E/I)balance is essential for normal neural development,behavior and cognition.E/I imbalance leads to a variety of neurological disorders,such as autism and schizophrenia.NMDA receptors(NMDARs)regulate AMPAR-mediated excitatory and GABAAR-mediated inhibitory synaptic transmission,suggesting that NMDARs play an important role in the establishment and maintenance of the E/I balance.In this review,we briefly introduced NMDARs,AMPARs and GABAARs,summarized the current studies on E/I balance mediated by NMDARs,and discussed the current advances in NMDAR-mediated AMPAR and GABAAR development.Specifically,we analyzed the role of NMDAR subunits in the establishment and maintenance of E/I balance,which may provide new therapeutic strategies for the recovery of E/I imbalance in neurological disorders.
基金supported by the National Basic Research Program of China (Grant No. J20110170)the National Natural Science Foundation of China (Grant Nos. 81000497 and 81071614)
文摘In the presence of glutamate and co-agonists, e.g., glycine, the N-methyl-D-aspartate receptor （NMDAR） plays an important role in physiological and pathophysiological brain processes. Previous studies indicate glycine could inhibit NMDAR respons- es induced by high concentration of NMDA in hippocampal neurons. The mechanism underlying this inhibitory impact, how- ever, has been unclear. In this study, the whole-cell patch-clamp recording and Ca2＋ imaging with Fluo-3/AM under laser scanning confocal microscope were used to analyze the possible involvement of NMDAR subnnits in this effect. We found that the peak current of NMDARs and Ca2＋ influx induced by high concentration of NMDA were reduced by treatment of gly- cine （0.03-10 I.tmol L-1） in a dose-dependent manner, and that the glycine-dependent inhibition of NMDAR responses, which were induced at 300 mol L-1 NMDA, was reversed by ZnCI2 through the blocking of the NR2A subunit of NMDARs, but was less influenced by ifenprodil, a NR2B inhibitor. Our results suggest that the glycine-dependent inactivation of NMDARs is potentially modulated by the regulatory subunit NR2A.
