title: Canonical transient receptor potential 3 channels activate NF-κB to mediate allergic airway disease via PKC-α/IκB-α and calcineurin/IκB-β pathways.
abstract: The purpose of this study was to determine the role of canonical transient receptor potential 3 (TRPC3) channel in allergen-induced airway disease (AIAD) and its underlying signaling mechanisms. The procedures included (1) intravenous injection of lentiviral TRPC3 channel or nonsilencing short hairpin ribonucleic acid (shRNA) to make the channel knockdown (KD) or control mice, (2) allergen sensitization/challenge to induce AIAD, (3) patch-clamp recording and Ca(2+) imaging to examine the channel activity, and (4) gene manipulations and other methods to determine the underlying signaling mechanisms. The findings are that (1) intravenous or intranasal delivery of TRPC3 channel lentiviral shRNAs or blocker 1-[4-[(2,3,3-trichloro-1-oxo-2-propen-1-yl)amino]phenyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid prevents AIAD in mice, (2) TRPC3 channel KD and overexpression, respectively, blocks and augments protein kinase C-α/nuclear factor of κ light polypeptide gene enhancer in B-cell inhibitor-α (PKC-α/IκB-α)-mediated or calcineurin/IκB-β-dependent, NF-κB-dependent allergen-induced airway smooth muscle cell (ASMC) hyperproliferation and cyclin D1 (an important cell proliferation molecule) induction, and (3) the changes of the major molecules of the PKC-α/IκBα- and calcineurin/IκB-β-dependent NF-κB signaling pathways are also observed in asthmatic human ASMCs. The conclusions are that TRPC3 channels plays an essential role in AIAD via the PKC-α/IκB-α- and calcineurin/IκB-β-dependent NF-κB signaling pathways, and lentiviral shRNA or inhibitor of TRPC3 channels may become novel and effective treatments for AIAD.
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Tengyao
authors.initials: T
authors.lastname: Song
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Yun-Min
authors.initials: YM
authors.lastname: Zheng
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Vincent
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Rosenberg
authors.affiliation: *Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, USA; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, USA; and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA wangy@mail.amc.edu.
authors.forename: Yong-Xiao
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000200:Action Potentials; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation; D002478:Cells, Cultured; D015316:Genetic Therapy; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy; D015290:Second Messenger Systems; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011720:Pyrazoles; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C559943:ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D011493:Protein Kinase C; D019703:Calcineurin
keywords: AIAD; ion channel; signaling pathway