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Antimycin A-induced mitochondrial dysfunction activates vagal sensory neurons via ROS-dependent activation of TRPA1 and ROS-independent activation of TRPV1.
Brain Res. 2019 07 15; 1715:94-105.BR

Abstract

Inflammation causes activation of nociceptive sensory nerves, resulting in debilitating sensations and reflexes. Inflammation also induces mitochondrial dysfunction through multiple mechanisms. Sensory nerve terminals are densely packed with mitochondria, suggesting that mitochondrial signaling may play a role in inflammation-induced nociception. We have previously shown that agents that induce mitochondrial dysfunction, such as antimycin A, activate a subset of nociceptive vagal sensory nerves that express transient receptor potential (TRP) channels ankyrin 1 (A1) and vanilloid 1 (V1). However, the mechanisms underlying these responses are incompletely understood. Here, we studied the contribution of TRPA1, TRPV1 and reactive oxygen species (ROS) to antimycin A-induced vagal sensory nerve activation in dissociated neurons and at the sensory terminals of bronchopulmonary C-fibers. Nociceptive neurons were defined chemically and genetically. Antimycin A-evoked activation of vagal nociceptors in a Fura2 Ca2+ assay correlated with TRPV1 responses compared to TRPA1 responses. Nociceptor activation was dependent on both TRP channels, with TRPV1 predominating in a majority of responding nociceptors and TRPA1 predominating only in nociceptors with the greatest responses. Surprisingly, both TRPA1 and TRPV1 were activated by H2O2 when expressed in HEK293. Nevertheless, targeting ROS had no effect of antimycin A-evoked TRPV1 activation in either HEK293 or vagal neurons. In contrast, targeting ROS inhibited antimycin A-evoked TRPA1 activation in HEK293, vagal neurons and bronchopulmonary C-fibers, and a ROS-insensitive TRPA1 mutant was completely insensitive to antimycin A. We therefore conclude that mitochondrial dysfunction activates vagal nociceptors by ROS-dependent (TRPA1) and ROS-independent (TRPV1) mechanisms.

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Authors+Show Affiliations

Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

Taylor-Clark TE

Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. Electronic address: ttaylorc@health.usf.edu.

MeSH

Action PotentialsAnimalsAntimycin ACalciumFemaleHEK293 CellsHumansMaleMiceMice, Inbred C57BLMice, KnockoutMitochondriaNociceptorsReactive Oxygen SpeciesSensory Receptor CellsTRPA1 Cation ChannelTRPV Cation ChannelsTransient Receptor Potential ChannelsVagus Nerve

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30914247

Citation

Stanford, Katherine R., et al. "Antimycin A-induced Mitochondrial Dysfunction Activates Vagal Sensory Neurons Via ROS-dependent Activation of TRPA1 and ROS-independent Activation of TRPV1." Brain Research, vol. 1715, 2019, pp. 94-105.

Stanford KR, Hadley SH, Barannikov I, et al. Antimycin A-induced mitochondrial dysfunction activates vagal sensory neurons via ROS-dependent activation of TRPA1 and ROS-independent activation of TRPV1. Brain Res. 2019;1715:94-105.

Stanford, K. R., Hadley, S. H., Barannikov, I., Ajmo, J. M., Bahia, P. K., & Taylor-Clark, T. E. (2019). Antimycin A-induced mitochondrial dysfunction activates vagal sensory neurons via ROS-dependent activation of TRPA1 and ROS-independent activation of TRPV1. Brain Research, 1715, 94-105. https://doi.org/10.1016/j.brainres.2019.03.029

Stanford KR, et al. Antimycin A-induced Mitochondrial Dysfunction Activates Vagal Sensory Neurons Via ROS-dependent Activation of TRPA1 and ROS-independent Activation of TRPV1. Brain Res. 2019 07 15;1715:94-105. PubMed PMID: 30914247.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Antimycin A-induced mitochondrial dysfunction activates vagal sensory neurons via ROS-dependent activation of TRPA1 and ROS-independent activation of TRPV1. AU - Stanford,Katherine R, AU - Hadley,Stephen H, AU - Barannikov,Ivan, AU - Ajmo,Joanne M, AU - Bahia,Parmvir K, AU - Taylor-Clark,Thomas E, Y1 - 2019/03/23/ PY - 2018/12/18/received PY - 2019/03/11/revised PY - 2019/03/23/accepted PY - 2019/3/28/pubmed PY - 2020/9/20/medline PY - 2019/3/28/entrez KW - Antimycin A KW - C-fiber KW - Mitochondria KW - Nociceptor KW - Reactive oxygen species KW - TRPA1 KW - TRPV1 KW - Vagal SP - 94 EP - 105 JF - Brain research JO - Brain Res VL - 1715 N2 - Inflammation causes activation of nociceptive sensory nerves, resulting in debilitating sensations and reflexes. Inflammation also induces mitochondrial dysfunction through multiple mechanisms. Sensory nerve terminals are densely packed with mitochondria, suggesting that mitochondrial signaling may play a role in inflammation-induced nociception. We have previously shown that agents that induce mitochondrial dysfunction, such as antimycin A, activate a subset of nociceptive vagal sensory nerves that express transient receptor potential (TRP) channels ankyrin 1 (A1) and vanilloid 1 (V1). However, the mechanisms underlying these responses are incompletely understood. Here, we studied the contribution of TRPA1, TRPV1 and reactive oxygen species (ROS) to antimycin A-induced vagal sensory nerve activation in dissociated neurons and at the sensory terminals of bronchopulmonary C-fibers. Nociceptive neurons were defined chemically and genetically. Antimycin A-evoked activation of vagal nociceptors in a Fura2 Ca2+ assay correlated with TRPV1 responses compared to TRPA1 responses. Nociceptor activation was dependent on both TRP channels, with TRPV1 predominating in a majority of responding nociceptors and TRPA1 predominating only in nociceptors with the greatest responses. Surprisingly, both TRPA1 and TRPV1 were activated by H2O2 when expressed in HEK293. Nevertheless, targeting ROS had no effect of antimycin A-evoked TRPV1 activation in either HEK293 or vagal neurons. In contrast, targeting ROS inhibited antimycin A-evoked TRPA1 activation in HEK293, vagal neurons and bronchopulmonary C-fibers, and a ROS-insensitive TRPA1 mutant was completely insensitive to antimycin A. We therefore conclude that mitochondrial dysfunction activates vagal nociceptors by ROS-dependent (TRPA1) and ROS-independent (TRPV1) mechanisms. SN - 1872-6240 UR - https://www.unboundmedicine.com/medline/citation/30914247/Antimycin_A_induced_mitochondrial_dysfunction_activates_vagal_sensory_neurons_via_ROS_dependent_activation_of_TRPA1_and_ROS_independent_activation_of_TRPV1_ DB - PRIME DP - Unbound Medicine ER -