Abstract
Excitotoxicity is classically attributed to Ca2+ influx through NMDA receptors (NMDAr), leading to production of nitric oxide by neuronal nitric oxide synthase and superoxide by mitochondria, which react to form highly cytotoxic peroxynitrite. More recent observations warrant revision of the classic view and help to explain some otherwise puzzling aspects of excitotoxic cell injury. Studies using pharmacological and genetic approaches show that superoxide produced by NMDAr activation originates primarily from NADPH oxidase rather than from mitochondria. As NADPH oxidase is localized to the plasma membrane, this also provides an explanation for the extracellular release of superoxide and cell-to-cell “spread” of excitotoxic injury observed in vitro and in vivo. The signaling pathway linking NMDAr to NADPH oxidase involves Ca2+ influx, phosphoinositol-3-kinase, and protein kinase Cζ, and interventions at any of these steps can prevent superoxide production and excitotoxic injury. Ca2+ influx specifically through NMDAr is normally required to induce excitotoxicity, through a mechanism presumed to involve privileged Ca2+ access to local signaling domains. However, experiments using selective blockade of the NMDAr ion channel and artificial reconstitution of Ca2+ by other routes indicate that the special effects of NMDAr activation are attributable instead to concurrent non-ionotropic NMDAr signaling by agonist binding to NMDAr. The non-ionotropic signaling driving NADPH oxidase activation is mediated in part by phosphoinositol-3-kinase binding to the C-terminal domain of GluN2B receptor subunits. These more recently identified aspects of excitotoxicity expand our appreciation of the complexity of excitotoxic processes and suggest novel approaches for limiting neuronal injury.
Highlights
The term “excitotoxicity” was first used in reference to rapid neuronal death caused by glutamate receptor activation (Olney et al, 1971)
The early observations that identified key roles for Ca2+, superoxide, and nitric oxide in excitotoxicity have stood the test of time, but subsequent observations have identified complexities that both expand our understanding of this process and open additional questions. Among these complexities is that elevations in either superoxide or nitric oxide levels can drive production of peroxynitrite, such that it is rarely possible to ascertain which one of these ROS is driving excitotoxic injury
It has been demonstrated that superoxide production induced by NMDA receptor (NMDAr) stimulation is generated primarily by NOX2, rather than mitochondria, but it remains uncertain whether this superoxide signal may be amplified by resultant mitochondrial dysfunction
Summary
The term “excitotoxicity” was first used in reference to rapid neuronal death caused by glutamate receptor activation (Olney et al, 1971). The present review focuses on aspects of rapid neuronal death induced by pathological stimulation of NMDA-type glutamate receptors. This process is widely attributed to Ca2+ influx, leading to superoxide and nitric oxide production, which together generate the cytotoxic reactive oxygen species, peroxynitrite. Recent studies have identified several additional complexities that challenge this classical view and identify novel ways to suppress excitotoxic neuronal death. These complexities arise from interactions between superoxide and nitric oxide, the sources of superoxide formation, and the newly appreciated role of non-ionotropic NMDA receptor (NMDAr) signaling. As further detailed in the section “Signaling pathways underlying NOX2 activation by NMDA receptors,” the issue gains significance because interventions that are thought to act by blocking nitric oxide formation may function by blocking superoxide formation, and vice versa
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
