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.