title: NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus.
abstract: Sigma-1 receptors (σ-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of σ-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 σ-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 σ-1R agonists (+)-SKF 10,047 [2S-(2α,6α,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 (+)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus. We also demonstrate that σ-1R activation leads to an increased interaction between GluN2 subunits and σ-1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that σ-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.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and.
authors.forename: Mohan
authors.initials: M
authors.lastname: Pabba
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and.
authors.forename: Adrian Y C
authors.initials: AY
authors.lastname: Wong
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and.
authors.forename: Nina
authors.initials: N
authors.lastname: Ahlskog
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and.
authors.forename: Elitza
authors.initials: E
authors.lastname: Hristova
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and.
authors.forename: Dante
authors.initials: D
authors.lastname: Biscaro
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and.
authors.forename: Wissam
authors.initials: W
authors.lastname: Nassrallah
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada, K1H 8M5.
authors.forename: Johnny K
authors.initials: JK
authors.lastname: Ngsee
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and.
authors.forename: Melissa
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada, K1H 8M5.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beique
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario, Canada, K1H 8M5, and rbergeron@ohri.ca.
authors.forename: Richard
authors.initials: R
authors.lastname: Bergeron
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D005029:Ethylenediamines / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D010423:Pentazocine / Q000494:pharmacology; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D017480:Receptors, sigma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D000076122:Disks Large Homolog 4 Protein; D005029:Ethylenediamines; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009025:Morpholines; D010423:Pentazocine; D010620:Phenazocine; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C501449:Dlg4 protein, rat; C121001:NR2B NMDA receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin; C012134:SK&F 10047
keywords: NMDA receptor; Western blot; protein synthesis; sigma-1 receptor; surface biotinylation; trafficking