Sensory Nerve Terminal Mitochondrial Dysfunction Activates Airway Sensory Nerves via Transient Receptor Potential (TRP) Channels

Nesuashvili, Lika; Hadley, Stephen; Bahia, Parmvir K.; Taylor‐Clark, Thomas E.

doi:10.1124/mol.112.084319

Cited by 46 publications

(72 citation statements)

References 59 publications

(133 reference statements)

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“…1A). Antimycin A (20 mM) evoked significant action potential discharge in TRPA1-expressing bronchopulmonary fibers via a ROS-dependent TRPA1 activation-this mechanism is described in our previous study (Nesuashvili et al, 2013). The direct activation of these TRPA1-expressing nerves lasted from 2 to 7 minutes; other fibers were not overtly activated.…”

Section: Resultsmentioning

confidence: 88%

“…In this preparation, the action potential discharge evoked in individual nerves by either mechanical or chemical stimuli to the airways can be quantified. Previous studies have shown that the majority of fibers innervating the lung are slowly conducting and express TRPA1 and TRPV1 (Nassenstein et al, 2008;Nesuashvili et al, 2013). This subset of nerves is thought to serve as nociceptors in the mouse airways.…”

Section: Resultsmentioning

confidence: 99%

“…Vagal ganglia were immediately isolated and enzymatically dissociated using previously described methods (Nesuashvili et al, 2013). Isolated neurons were plated onto poly (D-lysine)-and laminin-coated coverslips, incubated at 37°C in L-15 (supplemented with 10% fetal bovine serum), and used within 24 hours.…”

Section: Dissociation Of Mouse Vagal Gangliamentioning

confidence: 99%

“…This is likely of particular importance for the peripheral terminals of sensory nerves, which contain a high density of mitochondria (Hung et al, 1973;von During and Andres, 1988). We have previously shown an interaction between nerve terminal mitochondria and nerve terminal function in a study that demonstrated that mitochondrial ROS can cause overt bronchopulmonary C-fiber activation (action potential discharge) via the selective gating of transient receptor potential (TRP) ankyrin 1 (TRPA1) (Nesuashvili et al, 2013). It is not yet known whether mitochondrial ROS can also modulate neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

“…The innervated isolated lung preparation was prepared, as previously described (Nassenstein et al, 2008;Nesuashvili et al, 2013). Briefly, the airways and lungs with their intact extrinsic innervation (vagus nerve including vagal ganglia) were taken and placed in a dissecting dish containing Krebs bicarbonate buffer solution composed of the following (mM): 118 NaCl, 5.4 KCl, 1.0 NaH 2 PO 4 , 1.2 MgSO 4 , 1.9 CaCl 2 , 25.0 NaHCO 3 , and 11.1 D-glucose, and equilibrated with 95% O 2 and 5% CO 2 (pH 7.3-7.4) and containing 3 mM indomethacin.…”

Section: Bronchopulmonary C-fiber Extracellular Recordingsmentioning

confidence: 99%

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Sensory Nerve Terminal Mitochondrial Dysfunction Induces Hyperexcitability in Airway Nociceptors via Protein Kinase C

2014

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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 Q i 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 P2X 2/3 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, H 2 O 2 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.

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Dissociation Of Mouse Vagal Gangliamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Bronchopulmonary C-fiber Extracellular Recordingsmentioning

confidence: 99%

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Sensory Nerve Terminal Mitochondrial Dysfunction Induces Hyperexcitability in Airway Nociceptors via Protein Kinase C

2014

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Transient Receptor Potential Channels and Chronic Airway Inflammatory Diseases: A Comprehensive Review

Yang

Xia

Lou

et al. 2018

Lung

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Chronic airway inflammatory diseases remain a major problem worldwide, such that there is a need for additional therapeutic targets and novel drugs. Transient receptor potential (TRP) channels are a group of non-selective cation channels expressed throughout the body that are regulated by various stimuli. TRP channels have been identified in numerous cell types in the respiratory tract, including sensory neurons, airway epithelial cells, airway smooth muscle cells, and fibroblasts. Different types of TRP channels induce cough in sensory neurons via the vagus nerve. Permeability and cytokine production are also regulated by TRP channels in airway epithelial cells, and these channels also contribute to the modulation of bronchoconstriction. TRP channels may cooperate with other TRP channels, or act in concert with calcium-dependent potassium channels and calcium-activated chloride channel. Hence, TRP channels could be the potential therapeutic targets for chronic airway inflammatory diseases. In this review, we aim to discuss the expression profiles and physiological functions of TRP channels in the airway, and the roles they play in chronic airway inflammatory diseases.

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Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain

Sözbir

Nazıroğlu

2015

Metab Brain Dis

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N-acetylcysteine (NAC) is a sulfhydryl donor antioxidant that contributes to the regeneration of glutathione (GSH) and also scavengers via a direct reaction with free oxygen radicals. Recently, we observed a modulatory role of NAC on GSH-depleted dorsal root ganglion (DRG) cells in rats. NAC may have a protective role on oxidative stress and calcium influx through regulation of the TRPM2 channel in diabetic neurons. Therefore, we investigated the effects of NAC on DRG TRPM2 channel currents and brain oxidative stress in streptozotocin (STZ)-induced diabetic rats. Thirty-six rats divided into four groups: control, STZ, NAC and STZ + NAC. Diabetes was induced in the STZ and STZ + NAC groups by intraperitoneal STZ (65 mg/kg) administration. After the induction of diabetes, rats in the NAC and STZ + NAC groups received NAC (150 mg/kg) via gastric gavage. After 2 weeks, DRG neurons and the brain cortex were freshly isolated from rats. In whole-cell patch clamp experiments, TRPM2 currents in the DRG following diabetes induction with STZ were gated by H2O2. TRPM2 channel current densities in the DRG and lipid peroxidation levels in the DRG and brain were higher in the STZ groups than in controls; however, brain GSH, GSH peroxidase (GSH-Px), vitamin C and vitamin E concentrations and DRG GSH-Px activity were decreased by diabetes. STZ + H2O2-induced TRPM2 gating was totally inhibited by NAC and partially inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and 2-aminoethyl diphenylborinate (2-APB). GSH-Px activity and lipid peroxidation levels were also attenuated by NAC treatment. In conclusion, we observed a modulatory role of NAC on oxidative stress and Ca(2+) entry through the TRPM2 channel in the diabetic DRG and brain. Since excessive oxidative stress and overload Ca(2+) entry are common features of neuropathic pain, our findings are relevant to the etiology and treatment of pain neuropathology in DRG neurons.

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Sensory Nerve Terminal Mitochondrial Dysfunction Activates Airway Sensory Nerves via Transient Receptor Potential (TRP) Channels

Cited by 46 publications

References 59 publications

Sensory Nerve Terminal Mitochondrial Dysfunction Induces Hyperexcitability in Airway Nociceptors via Protein Kinase C

Sensory Nerve Terminal Mitochondrial Dysfunction Induces Hyperexcitability in Airway Nociceptors via Protein Kinase C

Transient Receptor Potential Channels and Chronic Airway Inflammatory Diseases: A Comprehensive Review

Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain

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