title: Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma.
abstract: Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single-nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution.
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Cassandra E
authors.initials: CE
authors.lastname: Deering-Rice
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Darien
authors.initials: D
authors.lastname: Shapiro
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Erin G
authors.initials: EG
authors.lastname: Romero
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.|2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Chris
authors.initials: C
authors.lastname: Stockmann
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Tatjana S
authors.initials: TS
authors.lastname: Bevans
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Quang M
authors.initials: QM
authors.lastname: Phan
authors.affiliation: 2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Stone
authors.affiliation: 2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fassl
authors.affiliation: 2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Flory
authors.initials: F
authors.lastname: Nkoy
authors.affiliation: 2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Uchida
authors.affiliation: 2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Ward
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.
authors.forename: John M
authors.initials: JM
authors.lastname: Veranth
authors.affiliation: 1 Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah; and.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reilly
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D060729:Coal Ash / Q000633:toxicity*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000502:physiology*; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D015220:Calcium Channels; D060729:Coal Ash; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; D001335:Vehicle Emissions
keywords: CFA; SNPs; TRPA1; diesel; lung