Sigma-1 and N-Methyl-d-Aspartate Receptors: A Partnership with Beneficial Outcomes.
Sigma-1 receptors (σ-1R) are interorganelle signaling molecules, which have been implicated in synaptic plasticity, primarily by enhancing the function of N-methyl-d-aspartate receptors (NMDARs). On the other hand, excessive influx of calcium via activated NMDAR can cause excitotoxicity. Yet, despite their NMDAR-enhancing role, multiple lines of evidence suggest that σ-1Rs are involved in neuroprotection. The mechanism underlying these intriguing opposing effects is not known. Recent studies now suggest the possibility that σ-1Rs could exert neuroprotective effects via targeted disruption of protein-protein interactions between NMDARs and their associated intracellular signaling machinery, specifically the neuronal nitric oxide synthase (nNOS). This targeted disruption of protein-protein interactions between NMDARs and nNOS results in lower levels of nitric oxide generation, thus having a neuroprotective effect. Here, we briefly summarize aspects of σ-1R-mediated enhancement of NMDAR function and possible neuroprotection. In-depth mechanistic understanding of σ-1R modulation of NMDAR function, which preserves Ca(2+) homoeostasis while limiting excitotoxicity would provide valuable information for designing novel as well as improving prevailing therapeutic strategies.
Neurobiology of Depression and Aging, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada.
Mohan
M
Pabba
Neurobiology of Depression and Aging, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada; Departments of Psychiatry, University of Toronto, Toronto, Ont., Canada; Departments of Pharmacology and Toxicology, University of Toronto, Toronto, Ont., Canada.
Etienne
E
Sibille
NMDA receptors; Neuroprotection; Schizophrenia; Sigma-1 receptor