Sigma-1 and N-Methyl-<smlcap>D</smlcap>-Aspartate Receptors: A Partnership with Beneficial Outcomes

Abstract

Sigma-1 receptors (σ-1R) are interorganelle signaling molecules, which have been implicated in synaptic plasticity, primarily by enhancing the function of N-methyl-<smlcap>D</smlcap>-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 Ca²⁺ homoeostasis while limiting excitotoxicity would provide valuable information for designing novel as well as improving prevailing therapeutic strategies.

Evaluation of 11C-NR2B-SMe and Its Enantiomers as PET Radioligands for Imaging the NR2B Subunit Within the NMDA Receptor Complex in Rats

“…Many ligands do not show selectivity for binding to NR2B over 1 receptors (15)(16)(17)(18)(19). In addition, 1 receptors exist in close proximity on cell membranes and may have direct interactions with NMDA receptors, modulating the behavior of NMDA receptor complexes (20).…”

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

“…In addition to influencing glutamate release, sigma-1 receptor activity is implicated in the neuronal responses to NMDA receptor stimulation, both directly, through interactions with specific subunits of the NMDA receptor [60, 61] and indirectly, through the modulation of other ion channels [62]. Sigma-1 receptors have been shown to bind to the cytosolic C-terminal region of the NMDA receptor NR1 subunit in recombinant cells, which can be inhibited by sigma-1 antagonists [63].…”

Genomic and Non-genomic Action of Neurosteroids in the Peripheral Nervous System

“…Moreover, sensory cranial ganglia synthesize glutamate (Malet and Brumovsky, 2015), while the SC possess the enzymatic machinery able to uptake and synthesize glutamate, like the excitatory amino acid transporter 1 (EAAC1) and glutamine synthetase (Miller et al, 2002;Perego et al, 2012). The σ1 receptor is an intracellular protein that localizes in membranes of the endoplasmic reticulum, plasmalemma, nucleus, and mitochondria (Alonso et al, 2000) and it is able to enhance NMDA activity (Pabba and Sibille, 2015). Activation of this receptor rises intracellular Ca ++ influx via NMDA (Hayashi et al, 2000), thus confirming the capability of σ1 to modulate NMDA receptor.…”