Heavy metals zinc, cadmium, and copper stimulate pulmonary sensory neurons via direct activation of TRPA1.
Airway exposure to zinc dust and zinc-containing ambient particulates can cause symptoms of airway irritation and inflammation, but the underlying molecular and cellular mechanisms are largely unknown. Transient receptor potential A1 (TRPA1) is selectively expressed in a subpopulation of pulmonary C-fiber afferents and has been considered as a major irritant sensor in the lung and airways. Using whole cell patch-clamp recording and Ca(2+) imaging, we have demonstrated that application of ZnCl(2) concentration dependently evoked inward current and Ca(2+) transient in isolated vagal pulmonary sensory neurons; both responses were almost completely inhibited after pretreatment with AP18, a specific TRPA1 antagonist. In anesthetized spontaneously breathing animals, intratracheal instillation of ZnCl(2) (2 mM, 25 microl) induced pronounced respiratory depression in wild-type mice, and the effect was essentially absent in TRPA1-deficient mice. In addition, our study showed that two other heavy metals, cadmium and copper, also stimulated pulmonary sensory neurons via a direct activation of TRPA1. In summary, our results suggest that activation of TRPA1 in pulmonary C-fiber sensory nerves may contribute to the respiratory toxicity induced by airway exposure to these three heavy metals.
Gu
Qihai
Q
Department of Physiology, University of Kentucky Medical Center, Lexington, Kentucky 40536-0298, USA. qgu2@email.uky.edu
Lin
Ruei-Lung
RL
D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017487:Ankyrins / Q000378:metabolism*; D019256:Cadmium Chloride / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002712:Chlorides / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D008168:Lung / Q000294:innervation* / Q000502:physiology; D008297:Male; D019216:Metals, Heavy / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels / Q000378:metabolism*; D017967:Zinc Compounds / Q000494:pharmacology
D017487:Ankyrins; D015220:Calcium Channels; D002712:Chlorides; D019216:Metals, Heavy; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; D017967:Zinc Compounds; D003300:Copper; C016837:zinc chloride; D019256:Cadmium Chloride; C029892:cupric chloride; D002118:Calcium