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dc.contributor.authorGriffith, Theanne N.  Concept link
dc.contributor.authorDocter, Trevor A.  Concept link
dc.contributor.authorLumpkin, Ellen A.  Concept link
dc.date.accessioned2019-10-09T14:53:06Z
dc.date.issued2019-09-04
dc.identifier.citationGriffith, T. N., Docter, T. A., & Lumpkin, E. A. (2019). Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons. Journal of Neuroscience, 39 (36), 7086-7101.en_US
dc.identifier.urihttps://hdl.handle.net/1912/24677
dc.description© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Neuroscience 39(36), (2019): 7086-7101, doi:10.1523/JNEUROSCI.2817-18.2019.en_US
dc.description.abstractSmall-diameter vesicular glutamate transporter 3-lineage (Vglut3lineage) dorsal root ganglion (DRG) neurons play an important role in mechanosensation and thermal hypersensitivity; however, little is known about their intrinsic electrical properties. We therefore set out to investigate mechanisms of excitability within this population. Calcium microfluorimetry analysis of male and female mouse DRG neurons demonstrated that the cooling compound menthol selectively activates a subset of Vglut3lineage neurons. Whole-cell recordings showed that small-diameter Vglut3lineage DRG neurons fire menthol-evoked action potentials and exhibited robust, transient receptor potential melastatin 8 (TRPM8)-dependent discharges at room temperature. This heightened excitability was confirmed by current-clamp and action potential phase-plot analyses, which showed menthol-sensitive Vglut3lineage neurons to have more depolarized membrane potentials, lower firing thresholds, and higher evoked firing frequencies compared with menthol-insensitive Vglut3lineage neurons. A biophysical analysis revealed voltage-gated sodium channel (NaV) currents in menthol-sensitive Vglut3lineage neurons were resistant to entry into slow inactivation compared with menthol-insensitive neurons. Multiplex in situ hybridization showed similar distributions of tetrodotoxin (TTX)-sensitive NaV transcripts between TRPM8-positive and -negative Vglut3lineage neurons; however, NaV1.8 transcripts, which encode TTX-resistant channels, were more prevalent in TRPM8-negative neurons. Conversely, pharmacological analyses identified distinct functional contributions of NaV subunits, with NaV1.1 driving firing in menthol-sensitive neurons, whereas other small-diameter Vglut3lineage neurons rely primarily on TTX-resistant NaV channels. Additionally, when NaV1.1 channels were blocked, the remaining NaV current readily entered into slow inactivation in menthol-sensitive Vglut3lineage neurons. Thus, these data demonstrate that TTX-sensitive NaVs drive action potential firing in menthol-sensitive sensory neurons and contribute to their heightened excitability.en_US
dc.description.sponsorshipThis work was supported by NIAMS R01AR051219 (E.A.L.). T.N.G. holds a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund and was supported by NHLBI T32HL120826. Core facilities were supported by the Columbia University EpiCURE Center (NIAMS P30AR069632) and the Thompson Family Foundation Initiative in CIPN and Sensory Neuroscience. This project was initiated during the MBL Neurobiology Course with support from NINDS R25NS063307. Dr. Blair Jenkins, Javier Marquina-Solis, and Dr. Adrian Thompson participated in preliminary studies at MBL. We thank Dr. Manu Ben-Johny and Dr. Lori Isom for sharing reagents, Dr. Irina Vetter for peptide toxins, Venesa Cuadrado for technical assistance, Rachel Clary for assistance with custom MATLAB routines, and Dr. Jon Sack and members of the Lumpkin laboratory for helpful discussions.en_US
dc.publisherSociety for Neuroscienceen_US
dc.relation.urihttps://doi.org/10.1523/JNEUROSCI.2817-18.2019
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectaction potentialen_US
dc.subjectdorsal root ganglionen_US
dc.subjectexcitabilityen_US
dc.subjectsensory neuronen_US
dc.subjectsodium channelen_US
dc.titleTetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neuronsen_US
dc.typeArticleen_US
dc.description.embargo2020-01-03en_US
dc.identifier.doi10.1523/JNEUROSCI.2817-18.2019
dc.embargo.liftdate2020-01-03


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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International