title: 17β-Estradiol inhibits phosphorylation of stromal interaction molecule 1 (STIM1) protein: implication for store-operated calcium entry and chronic lung diseases.
abstract: Sex plays a significant role in the development of lung diseases including asthma, cancer, chronic bronchitis, and cystic fibrosis. In cystic fibrosis, 17β-estradiol (E2) may inhibit store-operated Ca(2+) entry (SOCE) to impinge upon airway secretions, leaving females at greater risk of contracting lung infections. Stromal interaction molecule 1 (STIM1)-mediated SOCE is essential for cell homeostasis and regulates numerous processes including cell proliferation, smooth muscle contraction, and secretion. E2 can signal nongenomically to modulate Ca(2+) signaling, but little is known of the underlying mechanisms. We found that E2 exposure inhibited STIM1 translocation in airway epithelia, preventing SOCE. This correlated with a decrease in STIM1-STIM1 FRET and STIM1 mobility in E2-exposed HEK293T cells co-expressing estrogen receptor α. We also examined the role of STIM1 phosphorylation in E2-mediated inhibition of STIM1 mobility. STIM1 is basally phosphorylated at serine 575, which is required for SOCE. Exposure to E2 significantly decreased STIM1 serine phosphorylation. Mutating serine 575 to an alanine blocked STIM1 phosphorylation, reduced basal STIM1 mobility, and rendered STIM1 insensitive to E2. These data indicate that E2 can signal nongenomically by inhibiting basal phosphorylation of STIM1, leading to a reduction in SOCE.
authors.affiliation: Department of Cell and Molecular Physiology, the University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: John T
authors.initials: JT
authors.lastname: Sheridan
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, the University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Rodney C
authors.initials: RC
authors.lastname: Gilmore
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, the University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Watson
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, the University of North Carolina, Chapel Hill, North Carolina 27599.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Archer
authors.affiliation: Department of Cell and Molecular Physiology, the University of North Carolina, Chapel Hill, North Carolina 27599; Cystic Fibrosis/Pulmonary Research and Treatment Center, the University of North Carolina, Chapel Hill, North Carolina 27599. Electronic address: tarran@med.unc.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Tarran
mesh_terms: D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D005260:Female; D006801:Humans; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000071737:Stromal Interaction Molecule 1
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D004958:Estradiol; D002118:Calcium
keywords: Calcium; Cystic Fibrosis; Epithelial Cell; Estrogen; Phosphorylation