Sigma-1 receptors (-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of -1Rs is their ability to interact and modulate a large number of voltage-and ligand-gated ion channels at the plasma membrane. We have reported previously that agonists for -1Rs potentiate NMDA receptor (NMDAR) currents, although the mechanism by which this occurs is still unclear. In this study, we show that in vivo administration of the selective -1R agonists (ϩ)-SKF 10,047 [2S-(2␣,6␣,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (N-allylnormetazocine) hydrochloride], PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate hydrochloride), and (ϩ)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus. We also demonstrate that -1R activation leads to an increased interaction between GluN2 subunits and -1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that -1R may play an important role in NMDAR-mediated functions, such as learning and memory. It also opens new avenues for additional studies into a multitude of pathological conditions in which NMDARs are involved, including schizophrenia, dementia, and stroke.

The sigma-1 receptor (s-1R) is an endoplasmic reticulum resident chaperone protein involved in a plethora of cellular functions, and whose disruption has been implicated in a wide range of diseases. Genetic analysis has revealed two s-1R mutants involved in neuromuscular disorders. A point mutation (E102Q) in the ligand-binding domain results in the juvenile form of amyotrophic lateral sclerosis (ALS16), and a 20 amino-acid deletion (D31-50) in the putative cytosolic domain leads to a form of distal hereditary motor neuropathy. We investigated the localization and functional properties of these mutants in cell lines using confocal imaging and electrophysiology. The s-1R mutants exhibited a significant increase in mobility, aberrant localization, and enhanced block of the inwardly rectifying K 1 channel K ir 2.1, compared with the wild-type s-1R. Thus, these s-1R mutants have different functional properties that could contribute to their disease phenotypes.

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