Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma

• DOI: 10.1165/rcmb.2015-0086oc
• Publication Date: 2015-06-03T16:45:31Z
• Authors: Cassandra E. Deer...; Darien Shapiro; Erin G. Romero; Chris Stockmann; Tatjana S. Bevans; Quang M. Phan; Bryan L. Stone; Bernhard Fassl; Flory Nkoy; Derek A. Uchida; Robert M. Ward; John M. Veranth; Christopher A. Re...
• Keywords: Ankyrin repeat; Ankyrin; HEK 293 cells

Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated the pathogenesis of asthma. Our hypothesis was that particulate materials via a mechanism distinct from chemical agonists that, cohort children with asthma living location prone to high levels air pollution, expression uniquely sensitive forms may correlate reduced control. Variant were constructed by mutating residues known functional elements corresponding single-nucleotide polymorphisms domains. activity studied transfected HEK-293 cells using allyl-isothiocynate, model soluble electrophilic agonist; 3,5-ditert butylphenol, nonelectrophilic agonist component diesel exhaust particles; insoluble coal fly ash (CFA) particles. The N-terminal variants R3C R58T exhibited greater, but not additive, all three agonists. ankyrin repeat domain-4 single nucleotide E179K K186N decreased response CFA. predicted N-linked glycosylation site N747A N753A responses CFA, which attributable differences cellular localization. pore-loop residue R919Q comparable wild-type, whereas N954T inactive These data identify roles for domain-4, cell surface glycans, selected domain activation Furthermore, correlated control some children, suggest modulate asthma, particularly among individuals locations pollution.