title: STIM1 regulates platelet-derived growth factor-induced migration and Ca2+ influx in human airway smooth muscle cells.
abstract: It is suggested that migration of airway smooth muscle (ASM) cells plays an important role in the pathogenesis of airway remodeling in asthma. Increases in intracellular Ca(2+) concentrations ([Ca(2+)](i)) regulate most ASM cell functions related to asthma, such as contraction and proliferation. Recently, STIM1 was identified as a sarcoplasmic reticulum (SR) Ca(2+) sensor that activates Orai1, the Ca(2+) channel responsible for store-operated Ca(2+) entry (SOCE). We investigated the role of STIM1 in [Ca(2+)](i) and cell migration induced by platelet-derived growth factor (PDGF)-BB in human ASM cells. Cell migration was assessed by a chemotaxis chamber assay. Human ASM cells express STIM1, STIM2, and Orai1 mRNAs. SOCE activated by thapsigargin, an inhibitor of SR Ca(2+)-ATPase, was significantly blocked by STIM1 siRNA and Orai1 siRNA but not by STIM2 siRNA. PDGF-BB induced a transient increase in [Ca(2+)](i) followed by sustained [Ca(2+)](i) elevation. Sustained increases in [Ca(2+)](i) due to PDGF-BB were significantly inhibited by a Ca(2+) chelating agent EGTA or by siRNA for STIM1 or Orai1. The numbers of migrating cells were significantly increased by PDGF-BB treatment for 6 h. Knockdown of STIM1 and Orai1 by siRNA transfection inhibited PDGF-induced cell migration. Similarly, EGTA significantly inhibited PDGF-induced cell migration. In contrast, transfection with siRNA for STIM2 did not inhibit the sustained elevation of [Ca(2+)](i) or cell migration induced by PDGF-BB. These results demonstrate that STIM1 and Orai1 are essential for PDGF-induced cell migration and Ca(2+) influx in human ASM cells. STIM1 could be an important molecule responsible for airway remodeling.
authors.affiliation: Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Suganuma
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Aso
authors.forename: Masashi
authors.initials: M
authors.lastname: Kondo
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sokabe
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D000077214:Becaplermin; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D000071740:ORAI1 Protein; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D020574:Proto-Oncogene Proteins c-sis; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D000077214:Becaplermin; D004533:Egtazic Acid; D019284:Thapsigargin; D002118:Calcium