Abstract
Excessive activation of N-methyl-d-aspartic acid (NMDA) receptors after cerebral ischemia is a key cause of ischemic injury. For a long time, it was generally accepted that calcium influx is a necessary condition for ischemic injury mediated by NMDA receptors. However, recent studies have shown that NMDA receptor signaling, independent of ion flow, plays an important role in the regulation of ischemic brain injury. The purpose of this review is to better understand the roles of metabotropic NMDA receptor signaling in cerebral ischemia and to discuss the research and development directions of NMDA receptor antagonists against cerebral ischemia. This mini review provides a discussion on how metabotropic transduction is mediated by the NMDA receptor, related signaling molecules, and roles of metabotropic NMDA receptor signaling in cerebral ischemia. In view of the important roles of metabotropic signaling in cerebral ischemia, NMDA receptor antagonists, such as GluN2B-selective antagonists, which can effectively block both pro-death metabotropic and pro-death ionotropic signaling, may have better application prospects.
Highlights
Glutamate receptors mediate glutamate’s excitatory role in physiological processes such as memory, learning, and synaptic plasticity (Hansen et al, 2021); they play a part in several common neurological diseases, such as depression (Xia et al, 2021), Alzheimer’s disease (Srivastava et al, 2020) and epilepsy (Alcoreza et al, 2021)
Metabotropic N-methyl-D-aspartic acid (NMDA) receptor signaling, which is independent of ion flow, is involved in long-term depression (LTD) (Nabavi et al, 2013), synaptic depression induced by β-amyloid (Aβ) (Kessels et al, 2013; Tamburri et al, 2013; Birnbaum et al, 2015), dendritic spine shrinkage (Stein et al, 2015; Stein et al, 2020) and long-term potentiation (LTP)-induced spine growth (Stein et al, 2021)
Neuronal nitric oxide synthase/nitric oxide synthase one adaptor protein (NOS1AP)/p38/MAPK-activated protein kinase 2 (MK2)/cofilin is a key metabotropic NMDA receptor signaling pathway for gating the structural plasticity of dendritic spines. nNOS is a member of the NMDA receptor complex that anchors to the scaffold protein postsynaptic density-95 (PSD-95) (Sun et al, 2015)
Summary
Glutamate receptors mediate glutamate’s excitatory role in physiological processes such as memory, learning, and synaptic plasticity (Hansen et al, 2021); they play a part in several common neurological diseases, such as depression (Xia et al, 2021), Alzheimer’s disease (Srivastava et al, 2020) and epilepsy (Alcoreza et al, 2021). Metabotropic NMDA receptor signaling has not been found in some other important processes, such as spike timing-dependent plasticity (Rodriguez-Moreno and Paulsen, 2008; Banerjee et al, 2014; Andrade-Talavera et al, 2016) and presynaptic glutamate release modulation (Abrahamsson et al, 2017; PriusMengual et al, 2019). This mini review provides a discussion on how metabotropic transduction is mediated by the NMDA receptor, known related signaling molecules, and their interplay in cerebral ischemia
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