title: Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1.
abstract: Sigma1 receptors (σ1Rs) are expressed widely; they bind diverse ligands, including psychotropic drugs and steroids, regulate many ion channels, and are implicated in cancer and addiction. It is not known how σ1Rs exert such varied effects. We demonstrate that σ1Rs inhibit store-operated Ca(2+)entry (SOCE), a major Ca(2+)influx pathway, and reduce the Ca(2+)content of the intracellular stores. SOCE was inhibited by expression of σ1R or an agonist of σ1R and enhanced by loss of σ1R or an antagonist. Within the endoplasmic reticulum (ER), σ1R associated with STIM1, the ER Ca(2+)sensor that regulates SOCE. This interaction was modulated by σ1R ligands. After depletion of Ca(2+)stores, σ1R accompanied STIM1 to ER-plasma membrane (PM) junctions where STIM1 stimulated opening of the Ca(2+)channel, Orai1. The association of STIM1 with σ1R slowed the recruitment of STIM1 to ER-PM junctions and reduced binding of STIM1 to PM Orai1. We conclude that σ1R attenuates STIM1 coupling to Orai1 and thereby inhibits SOCE.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, England, UK.
authors.forename: Shyam
authors.initials: S
authors.lastname: Srivats
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, England, UK.
authors.forename: Dilshan
authors.initials: D
authors.lastname: Balasuriya
authors.affiliation: MRC Laboratory for Molecular Biology, Cambridge CB2 0QH, England, UK.
authors.forename: Mathias
authors.initials: M
authors.lastname: Pasche
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, England, UK.
authors.forename: Gerard
authors.initials: G
authors.lastname: Vistal
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, England, UK.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Edwardson
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, England, UK.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, England, UK Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton BN1 9QG, England, UK R.Murrell-Lagnado@sussex.ac.uk.
authors.forename: Ruth D
authors.initials: RD
authors.lastname: Murrell-Lagnado
mesh_terms: D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D000071740:ORAI1 Protein; D017480:Receptors, sigma / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; D017480:Receptors, sigma; D000071737:Stromal Interaction Molecule 1; D000097605:Sigma-1 Receptor; C510746:ORAI1 protein, human; C103530:STIM1 protein, human