Abstract
Airway sensory nerve excitability is a key determinant of respiratory disease-associated reflexes and sensations such as cough and dyspnea. Inflammatory signaling modulates mitochondrial function and produces reactive oxygen species (ROS). Peripheral terminals of sensory nerves are densely packed with mitochondria; thus, we hypothesized that mitochondrial modulation would alter neuronal excitability. We recorded action potential firing from the terminals of individual bronchopulmonary C-fibers using a mouse ex vivo lung-vagal ganglia preparation. C-fibers were characterized as nociceptors or non-nociceptors based upon conduction velocity and response to transient receptor potential (TRP) channel agonists. Antimycin A (mitochondrial complex III Qi site inhibitor) had no effect on the excitability of non-nociceptors. However, antimycin A increased excitability in nociceptive C-fibers, decreasing the mechanical threshold by 50% and increasing the action potential firing elicited by a P2X2/3 agonist to 270% of control. Antimycin A–induced nociceptor hyperexcitability was independent of TRP ankyrin 1 or TRP vanilloid 1 channels. Blocking mitochondrial ATP production with oligomycin or myxothiazol had no effect on excitability. Antimycin A–induced hyperexcitability was dependent on mitochondrial ROS and was blocked by intracellular antioxidants. ROS are known to activate protein kinase C (PKC). Antimycin A–induced hyperexcitability was inhibited by the PKC inhibitor bisindolylmaleimide (BIM) I, but not by its inactive analog BIM V. In dissociated vagal neurons, antimycin A caused ROS-dependent PKC translocation to the membrane. Finally, H2O2 also induced PKC-dependent nociceptive C-fiber hyperexcitability and PKC translocation. In conclusion, ROS evoked by mitochondrial dysfunction caused nociceptor hyperexcitability via the translocation and activation of PKC.
Footnotes
- Received December 11, 2013.
- Accepted March 18, 2014.
This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R00-HL088520 and R01-HL119802].
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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