TRPA1 is a major oxidant sensor in murine airway sensory neurons
Bret F. Bessac, … , Lauren Cohn, Sven-Eric Jordt
Bret F. Bessac, … , Lauren Cohn, Sven-Eric Jordt
Published April 8, 2008
Citation Information: J Clin Invest. 2008;118(5):1899-1910. https://doi.org/10.1172/JCI34192.
View: Text | PDF
Research Article Article has an altmetric score of 15

TRPA1 is a major oxidant sensor in murine airway sensory neurons

Abstract

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 Ca2+ 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.

Authors

Bret F. Bessac, Michael Sivula, Christian A. von Hehn, Jasmine Escalera, Lauren Cohn, Sven-Eric Jordt

×

Figure 3

Lack of NaOCl-induced Ca2+ influx in sensory neurons and respiratory insensitivity to NaOCl aerosol in Trpa1–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Lack of NaOCl-induced Ca2+ influx in sensory neurons and respiratory ins...
(A) Responses of cultured DRG neurons from littermate Trpa1+/+ and Trpa1–/– mice to NaOCl (24 ppm) followed by 5 μM capsaicin, as measured by Fura-2 imaging. Trpa1–/– neurons showed no [Ca2+]i increase after NaOCl exposure, but were activated by capsaicin. Pseudocolors denote 0–3 μM [Ca2+]i. (B) Activation of Ca2+ influx into DRG neurons plotted against time. Average [Ca2+]i concentration of neurons activated by application of NaOCl followed by mustard oil, capsaicin, and 65 mM KCl. Thick and thin lines denote mean and ± SEM, respectively. Neurons (n = 300 [Trpa1+/+]; 263 [Trpa1–/–]) cultured from 4 mice per group were analyzed at ×10 magnification. (C) Effects of exposure to NaOCl aerosol on respiratory frequencies, as measured by unrestrained plethysmography. Mice were exposed to vehicle aerosol (10 min), room air flush (2 min), NaOCl aerosol (15 min), and then air (8 min). Values denote percentage of baseline (initial vehicle exposure). Respiratory frequency was slightly affected in Trpa1–/– mice, but dramatically declined in Trpa1+/+ mice during NaOCl exposure and when NaOCl aerosol was replaced by air. Error bars denote SEM. P < 0.00005 between groups; P < 0.000001 over time (repeated-measures ANOVA). n = 11 per group. (D) EEP duration during exposure to NaOCl aerosol. Data were collected from the experiment described in C. Unlike Trpa1–/– mice, Trpa1+/+ mice responded to NaOCl aerosol with an approximately 3-fold increase in EEP duration, which remained elevated 8 min after the end of NaOCl exposure. P < 0.000001 between groups, over time, and for the interaction of genotype and time (repeated-measures ANOVA). Single asterisks denote significant differences (Bonferroni post-hoc analysis; α = 0.05) for individual time points.