title: STIM2 enhances receptor-stimulated Ca²⁺ signaling by promoting recruitment of STIM1 to the endoplasmic reticulum-plasma membrane junctions.
abstract: A central component of receptor-evoked Ca(2+) signaling is store-operated Ca(2+) entry (SOCE), which is activated by the assembly of STIM1-Orai1 channels in endoplasmic reticulum (ER) and plasma membrane (PM) (ER-PM) junctions in response to depletion of ER Ca(2+). We report that STIM2 enhances agonist-mediated activation of SOCE by promoting STIM1 clustering in ER-PM junctions at low stimulus intensities. Targeted deletion of STIM2 in mouse salivary glands diminished fluid secretion in vivo and SOCE activation in dispersed salivary acinar cells stimulated with low concentrations of muscarinic receptor agonists. STIM2 knockdown in human embryonic kidney (HEK) 293 cells diminished agonist-induced Ca(2+) signaling and nuclear translocation of NFAT (nuclear factor of activated T cells). STIM2 lacking five carboxyl-terminal amino acid residues did not promote formation of STIM1 puncta at low concentrations of agonist, whereas coexpression of STIM2 with STIM1 mutant lacking the polybasic region STIM1ΔK resulted in co-clustering of both proteins. Together, our findings suggest that STIM2 recruits STIM1 to ER-PM junctions at low stimulus intensities when ER Ca(2+) stores are mildly depleted, thus increasing the sensitivity of Ca(2+) signaling to agonists.
authors.affiliation: Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Hwei Ling
authors.initials: HL
authors.lastname: Ong
authors.affiliation: Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Lorena Brito
authors.initials: LB
authors.lastname: de Souza
authors.affiliation: Translational Research Core, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, MD 20892, USA.
authors.forename: Changyu
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Kwong Tai
authors.initials: KT
authors.lastname: Cheng
authors.affiliation: Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Xibao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Translational Research Core, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, MD 20892, USA.
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Goldsmith
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
authors.affiliation: Secretory Physiology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), Bethesda, MD 20892, USA. indu.ambudkar@nih.gov.
authors.forename: Indu S
authors.initials: IS
authors.lastname: Ambudkar
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001426:Bacterial Proteins; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008164:Luminescent Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D012463:Saliva / Q000166:cytology; D017422:Sequence Analysis, DNA; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2
chemical_list: D001426:Bacterial Proteins; D015815:Cell Adhesion Molecules; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; C054562:yellow fluorescent protein, Bacteria