Tetrodotoxin-sensitive sodium channels mediate action potential firing and excitability in menthol-sensitive Vglut3-lineage sensory neurons
Griffith, Theanne N.
Docter, Trevor A.
Lumpkin, Ellen A.
MetadataShow full item record
Small-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.
© 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.
The publisher requires that this item be embargoed until 2020-01-03. Please check back after 2020-01-03.
Suggested 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.
The following license files are associated with this item:
Showing items related by title, author, creator and subject.
Voltage-gated calcium channel subunits from platyhelminths : potential role in praziquantel action Jeziorski, Michael C.; Greenberg, Robert M. (2006-02-07)Voltage-gated calcium (Ca2+) channels provide the pathway for Ca2+ influxes that underlie Ca2+-dependent responses in muscles, nerves, and other excitable cells. They are also targets of a wide variety of drugs and toxins. ...
Sodium dynamics in pyramidal neuron dendritic spines : synaptically evoked entry predominantly through AMPA receptors and removal by diffusion Miyazaki, Kenichi; Ross, William N. (Society for Neuroscience, 2017-10-11)Dendritic spines are key elements underlying synaptic integration and cellular plasticity, but many features of these important structures are not known or are controversial. We examined these properties using newly developed ...
Barzilai, Maya Gur; Reitzel, Adam M.; Kraus, Johanna E. M.; Gordon, Dalia; Technau, Ulrich; Gurevitz, Michael; Moran, Yehu (Cell Press, 2012-08-30)Ion selectivity of metazoan voltage-gated Na+ channels is critical for neuronal signaling and has long been attributed to a ring of four conserved amino acids that constitute the ion selectivity filter (SF) at the channel ...