title: Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal.
abstract: Transient receptor potential (TRP) A1 channels are cation channels found preferentially on nociceptive sensory neurones, including capsaicin-sensitive TRPV1-expressing vagal bronchopulmonary C-fibres, and are activated by electrophilic compounds such as mustard oil and cinnamaldehyde. Oxidative stress, a pathological feature of many respiratory diseases, causes the endogenous formation of a number of reactive electrophilic alkenals via lipid peroxidation. One such alkenal, 4-hydroxynonenal (4HNE), activates TRPA1 in cultured sensory neurones. However, our data demonstrate that 100 microm 4HNE was unable to evoke significant action potential discharge or tachykinin release from bronchopulmonary C-fibre terminals. Instead, another endogenously produced alkenal, 4-oxononenal (4ONE, 10 microm), which is far more electrophilic than 4HNE, caused substantial action potential discharge and tachykinin release from bronchopulmonary C-fibre terminals. The activation of mouse bronchopulmonary C-fibre terminals by 4ONE (10-100 microm) was mediated entirely by TRPA1 channels, based on the absence of responses in C-fibre terminals from TRPA1 knockout mice. Interestingly, although the robust increases in calcium caused by 4ONE (0.1-10 microm) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 microm 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 microm) was shown to activate TRPV1 channel-expressing HEK cells. In conclusion, the data support the hypothesis that 4-ONE is a relevant endogenous activator of vagal C-fibres via an interaction with TRPA1, and at less relevant concentrations, it may activate nerves via TRPV1.
authors.affiliation: Division of Allergy & Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, MA, USA.
authors.forename: T E
authors.initials: TE
authors.lastname: Taylor-Clark
authors.forename: M A
authors.initials: MA
authors.lastname: McAlexander
authors.forename: C
authors.initials: C
authors.lastname: Nassenstein
authors.forename: S A
authors.initials: SA
authors.lastname: Sheardown
authors.forename: S
authors.initials: S
authors.lastname: Wilson
authors.forename: J
authors.initials: J
authors.lastname: Thornton
authors.forename: M J
authors.initials: MJ
authors.lastname: Carr
authors.forename: B J
authors.initials: BJ
authors.lastname: Undem
mesh_terms: D000200:Action Potentials; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D012898:Autacoids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008168:Lung / Q000294:innervation; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: C403894:4-oxo-2-nonenal; D000447:Aldehydes; D012898:Autacoids; D015220:Calcium Channels; 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; C475685:Trpa1 protein, mouse; D002211:Capsaicin; D002118:Calcium