title: STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane.
abstract: As the sole Ca2+ entry mechanism in a variety of non-excitable cells, store-operated calcium (SOC) influx is important in Ca2+ signalling and many other cellular processes. A calcium-release-activated calcium (CRAC) channel in T lymphocytes is the best-characterized SOC influx channel and is essential to the immune response, sustained activity of CRAC channels being required for gene expression and proliferation. The molecular identity and the gating mechanism of SOC and CRAC channels have remained elusive. Previously we identified Stim and the mammalian homologue STIM1 as essential components of CRAC channel activation in Drosophila S2 cells and human T lymphocytes. Here we show that the expression of EF-hand mutants of Stim or STIM1 activates CRAC channels constitutively without changing Ca2+ store content. By immunofluorescence, EM localization and surface biotinylation we show that STIM1 migrates from endoplasmic-reticulum-like sites to the plasma membrane upon depletion of the Ca2+ store. We propose that STIM1 functions as the missing link between Ca2+ store depletion and SOC influx, serving as a Ca2+ sensor that translocates upon store depletion to the plasma membrane to activate CRAC channels.
authors.affiliation: Department of Physiology and Biophysics and Center for Immunology, University of California, Irvine, California 92697, USA.
authors.forename: Shenyuan L
authors.initials: SL
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Jack
authors.initials: J
authors.lastname: Roos
authors.forename: J Ashot
authors.initials: JA
authors.lastname: Kozak
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Deerinck
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Stauderman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cahalan
mesh_terms: D000818:Animals; D019921:Biotinylation; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020832:EF Hand Motifs / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D017136:Ion Transport; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016253:Microscopy, Immunoelectron; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D021381:Protein Transport; D051381:Rats; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D029721:Drosophila Proteins; D008565:Membrane Proteins; C502662:Stim protein, Drosophila; D000071737:Stromal Interaction Molecule 1; D002118:Calcium