title: Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels.
abstract: Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca(2+) stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determinants of Ca(2+)-dependent responses, the underlying modulatory mechanisms are unclear. In this paper, we identify STIM2β, a highly conserved alternatively spliced isoform of STIM2, which, in contrast to all known STIM isoforms, is a potent inhibitor of SOCE. Although STIM2β does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. Analysis of STIM2β mutants and Orai1-STIM2β chimeras suggested that it actively inhibits SOCE through a sequence-specific allosteric interaction with Orai1. Our results reveal a previously unrecognized functional flexibility in the STIM protein family by which alternative splicing creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals.
authors.affiliation: Graduate Program in Biochemistry, Stanford University School of Medicine, Stanford, CA 94305 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Anshul
authors.initials: A
authors.lastname: Rana
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305 Graduate Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Michelle
authors.initials: M
authors.lastname: Yen
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305 Novartis Institutes for Biomedical Research, Boston, MA 02139.
authors.forename: Amir Masoud
authors.initials: AM
authors.lastname: Sadaghiani
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Seth
authors.initials: S
authors.lastname: Malmersjö
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 689-798, South Korea cypark@unist.ac.kr ricardo.dolmetsch@novartis.com rslewis@stanford.edu.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Park
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305 Novartis Institutes for Biomedical Research, Boston, MA 02139 cypark@unist.ac.kr ricardo.dolmetsch@novartis.com rslewis@stanford.edu.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305 cypark@unist.ac.kr ricardo.dolmetsch@novartis.com rslewis@stanford.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Lewis
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D000071740:ORAI1 Protein; D055503:Protein Multimerization / Q000502:physiology*; D000071738:Stromal Interaction Molecule 2
chemical_list: D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C513279:STIM2 protein, human; D000071738:Stromal Interaction Molecule 2