TRPA1 is a major oxidant sensor in murine airway sensory neurons.
Sensory neurons in the airways are finely tuned to respond to reactive chemicals threatening airway function and integrity. Nasal trigeminal nerve endings are particularly sensitive to oxidants formed in polluted air and during oxidative stress as well as to chlorine, which is frequently released in industrial and domestic accidents. Oxidant activation of airway neurons induces respiratory depression, nasal obstruction, sneezing, cough, and pain. While normally protective, chemosensory airway reflexes can provoke severe complications in patients affected by inflammatory airway conditions like rhinitis and asthma. Here, we showed that both hypochlorite, the oxidizing mediator of chlorine, and hydrogen peroxide, a reactive oxygen species, activated Ca(2+) influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1(-/-) mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide-induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo.
Bessac
Bret F
BF
Department of Pharmacology and Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Sivula
Michael
M
von Hehn
Christian A
CA
Escalera
Jasmine
J
Cohn
Lauren
L
Jordt
Sven-Eric
SE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009149:Mustard Plant / Q000378:metabolism; D009475:Neurons, Afferent / Q000166:cytology / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010938:Plant Oils / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism; D012973:Sodium Hypochlorite / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
D016877:Oxidants; D010938:Plant Oils; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D006861:Hydrogen Peroxide; D012973:Sodium Hypochlorite; D002118:Calcium; C027793:mustard oil