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J Physiol Volume 586, Number 14, 3447-3459, July 15, 2008 DOI: 10.1113/jphysiol.2008.153585
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NEUROSCIENCE

Relative contributions of TRPA1 and TRPV1 channels in the activation of vagal bronchopulmonary C-fibres by the endogenous autacoid 4-oxononenal

 T. E. Taylor-Clark1, M. A. McAlexander2, C. Nassenstein1, S. A. Sheardown3, S. Wilson3, J. Thornton3, M. J. Carr2 and B. J. Undem1

1 Division of Allergy & Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, MA, USA
2 Neuronal & Ion Channel Biology, Respiratory Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, PA, USA
3 Transgenics, Genotyping & Viral Vectors, GlaxoSmithKline Pharmaceuticals, Harlow, UK

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 µM 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 µM), 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 µM) 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 µM) in dissociated vagal neurones were essentially abolished in TRPA1 knockout mice, at 100 µM 4ONE caused a large TRPV1-dependent response. Furthermore, 4ONE (100 µM) 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.

(Received 5 March 2008; accepted after revision 16 May 2008; first published online 22 May 2008)
Corresponding author B. J. Undem. Division of Allergy & Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, MA, USA. Email: bundem{at}jhmi.edu

T. E. Taylor-Clark and M. A. McAlexander contributed equally to this work.


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