title: Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma.
abstract: Transient receptor potential (TRP) channels are activated by environmental particulate materials. We hypothesized that polymorphic variants of transient receptor potential vanilloid-1 (TRPV1) would be uniquely responsive to insoluble coal fly ash compared with the prototypical soluble agonist capsaicin. Furthermore, these changes would manifest as differences in lung cell responses to these agonists and perhaps correlate with changes in asthma symptom control. The TRPV1-I315M and -T469I variants were more responsive to capsaicin and coal fly ash. The I585V variant was less responsive to coal fly ash particles due to reduced translation of protein and an apparent role for Ile-585 in activation by particles. In HEK-293 cells, I585V had an inhibitory effect on wild-type TRPV1 expression, activation, and internalization/agonist-induced desensitization. In normal human bronchial epithelial cells, IL-8 secretion in response to coal fly ash treatment was reduced for cells heterozygous for TRPV1-I585V. Finally, both the I315M and I585V variants were associated with worse asthma symptom control with the effects of I315M manifesting in mild asthma and those of the I585V variant manifesting in severe, steroid-insensitive individuals. This effect may be due in part to increased transient receptor potential ankyrin-1 (TRPA1) expression by lung epithelial cells expressing the TRPV1-I585V variant. These findings suggest that specific molecular interactions control TRPV1 activation by particles, differential activation, and desensitization of TRPV1 by particles and/or other agonists, and cellular changes in the expression of TRPA1 as a result of I585V expression could contribute to variations in asthma symptom control.
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and.
authors.forename: Cassandra E
authors.identifier: http://orcid.org/0000-0002-2103-1194
authors.initials: CE
authors.lastname: Deering-Rice
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and.
authors.forename: Chris
authors.initials: C
authors.lastname: Stockmann
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and.
authors.forename: Erin G
authors.initials: EG
authors.lastname: Romero
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Lu
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and.
authors.forename: Darien
authors.initials: D
authors.lastname: Shapiro
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84108.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Stone
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84108.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fassl
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84108.
authors.forename: Flory
authors.initials: F
authors.lastname: Nkoy
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84108.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Uchida
authors.affiliation: Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84108.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Ward
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and.
authors.forename: John M
authors.initials: JM
authors.lastname: Veranth
authors.affiliation: From the Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 and Chris.Reilly@pharm.utah.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reilly
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D001249:Asthma / Q000235:genetics / Q000378:metabolism; D001980:Bronchi / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics; D002211:Capsaicin / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D060729:Coal Ash / Q000633:toxicity*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000235:genetics; D050051:Transient Receptor Potential Channels / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015220:Calcium Channels; D060729:Coal Ash; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D050051:Transient Receptor Potential Channels; D002211:Capsaicin
keywords: Western blot; asthma; inflammation; single nucleotide polymorphism (SNP); transient receptor potential channels (TRP channels)