PMID- 26373801 OWN - NLM STAT- MEDLINE DCOM- 20160607 LR - 20181113 IS - 1530-6860 (Electronic) IS - 0892-6638 (Print) IS - 0892-6638 (Linking) VI - 30 IP - 1 DP - 2016 Jan TI - Canonical transient receptor potential 3 channels activate NF-kappaB to mediate allergic airway disease via PKC-alpha/IkappaB-alpha and calcineurin/IkappaB-beta pathways. PG - 214-29 LID - 10.1096/fj.15-274860 [doi] AB - 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-alpha/nuclear factor of kappa light polypeptide gene enhancer in B-cell inhibitor-alpha (PKC-alpha/IkappaB-alpha)-mediated or calcineurin/IkappaB-beta-dependent, NF-kappaB-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-alpha/IkappaBalpha- and calcineurin/IkappaB-beta-dependent NF-kappaB signaling pathways are also observed in asthmatic human ASMCs. The conclusions are that TRPC3 channels plays an essential role in AIAD via the PKC-alpha/IkappaB-alpha- and calcineurin/IkappaB-beta-dependent NF-kappaB signaling pathways, and lentiviral shRNA or inhibitor of TRPC3 channels may become novel and effective treatments for AIAD. CI - (c) FASEB. FAU - Song, Tengyao AU - Song T AD - *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. FAU - Zheng, Yun-Min AU - Zheng YM AD - *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. FAU - Vincent, Peter A AU - Vincent PA AD - *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. FAU - Cai, Dongsheng AU - Cai D AD - *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. FAU - Rosenberg, Paul AU - Rosenberg P AD - *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. FAU - Wang, Yong-Xiao AU - Wang YX AD - *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. LA - eng GR - R01 HL122865/HL/NHLBI NIH HHS/United States GR - R01 HL108232/HL/NHLBI NIH HHS/United States GR - R01 HL075190/HL/NHLBI NIH HHS/United States GR - R01 HL071000/HL/NHLBI NIH HHS/United States GR - HL071000/HL/NHLBI NIH HHS/United States GR - HL108232/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150915 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (I-kappa B Proteins) RN - 0 (NF-kappa B) RN - 0 (NFKBIA protein, human) RN - 0 (Nfkbia protein, mouse) RN - 0 (Pyrazoles) RN - 0 (TRPC Cation Channels) RN - 0 (TRPC3 cation channel) RN - 0 (ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - EC 2.7.11.10 (I-kappa B Kinase) RN - EC 2.7.11.10 (Ikbkb protein, mouse) RN - EC 2.7.11.13 (Protein Kinase C) RN - EC 3.1.3.16 (Calcineurin) SB - IM MH - Action Potentials MH - Animals MH - Calcineurin/metabolism MH - Calcium Signaling MH - Cell Proliferation MH - Cells, Cultured MH - Genetic Therapy MH - I-kappa B Kinase/metabolism MH - I-kappa B Proteins/metabolism MH - Mice MH - Myocytes, Smooth Muscle/drug effects/metabolism MH - NF-KappaB Inhibitor alpha MH - NF-kappa B/genetics/*metabolism MH - Protein Kinase C/metabolism MH - Pyrazoles/pharmacology/therapeutic use MH - Respiratory Hypersensitivity/drug therapy/*metabolism/therapy MH - Second Messenger Systems MH - TRPC Cation Channels/antagonists & inhibitors/*genetics/metabolism PMC - PMC4684550 OTO - NOTNLM OT - AIAD OT - ion channel OT - signaling pathway EDAT- 2015/09/17 06:00 MHDA- 2016/06/09 06:00 PMCR- 2017/01/01 CRDT- 2015/09/17 06:00 PHST- 2015/04/28 00:00 [received] PHST- 2015/08/31 00:00 [accepted] PHST- 2015/09/17 06:00 [entrez] PHST- 2015/09/17 06:00 [pubmed] PHST- 2016/06/09 06:00 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - fj.15-274860 [pii] AID - FJ_274860 [pii] AID - 10.1096/fj.15-274860 [doi] PST - ppublish SO - FASEB J. 2016 Jan;30(1):214-29. doi: 10.1096/fj.15-274860. Epub 2015 Sep 15.