Reduced Nav1.6 sodium channel activity in mice increases in vivo sensitivity to volatile anesthetics
Open accessAbstract
Nav1.6 is a major voltage-gated sodium channel in the central and peripheral nervous systems. Within neurons, the channel protein is concentrated at the axon initial segment and nodes of Ranvier, where it functions in initiation and propagation of action potentials. We examined the role of Nav1.6 in general anesthesia using two mouse mutants with reduced activity of Nav1.6, Scn8amedJ/medJ and Scn8a9J/9J. The mice were exposed to the general anesthetics isoflurane and sevoflurane in step-wise increments; the concentration required to produce loss of righting reflex, a surrogate for anesthetic-induced unconsciousness in rodents, was determined. Mice homozygous for these mutations exhibited increased sensitivity to both isoflurane and sevoflurane. The increased sensitivity was observed during induction of unconsciousness but not during the recovery phase, suggesting that the effect is not attributable to compromised systemic physiology. Electroencephalographic theta power during baseline waking was lower in mutants, suggesting decreased arousal and reduced neuronal excitability. This is the first report linking reduced activity of a specific voltage-gated sodium channel to increased sensitivity to general anesthetics in vivo.
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Mice with targeted knockdown of Nav1.6 show marked hypersensitivity to induction of isoflurane and sevoflurane anesthesia compared with wild-type siblings.
“mice with targeted knockdown of Nav1.6—the most abundant channel subtype in the CNS—exhibited a marked hypersensitivity to induction of both isoflurane and sevoflurane anesthesia when compared with their wild-type siblings [73].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [73]
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Cites
General Anesthesia, Sleep, and Coma
Brown, E. N., Lydic, R., & Schiff, N. D. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0808281 · Cited by 1,346 · see citing works
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal
Franks, N. P. (2008) · Nature reviews. Neuroscience · doi:10.1038/nrn2372 · Cited by 1,266 · see citing works
Electroencephalogram signatures of loss and recovery of consciousness from propofol
Purdon, P. L., Pierce, E. T., Mukamel, E. A., Prerau, M. J., Walsh, J. L., Wong, K. F. K., Salazar-Gomez, A. F., Harrell, P. G., Sampson, A. L., Cimenser, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221180110 · Cited by 854 · see citing works
Distinct contributions of Nav1.6 and Nav1.2 in action potential initiation and backpropagation
Hu, W., Tian, C., Li, T., Yang, M., Hou, H., & Shu, Y. (2009) · Nature Neuroscience · doi:10.1038/nn.2359 · Cited by 706 · see citing works
Sodium channel Na <sub>v</sub> 1.6 is localized at nodes of Ranvier, dendrites, and synapses
Caldwell, J. H., Schaller, K. L., Lasher, R. S., Peles, E., & Levinson, S. R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090034797 · Cited by 649 · see citing works
Raman, I. M., Sprunger, L. K., Meisler, M. H., & Bean, B. P. (1997) · Neuron · doi:10.1016/s0896-6273(00)80969-1 · Cited by 390 · see citing works
Self-citationCell-type-dependent molecular composition of the axon initial segment
Lorincz, A., & Nusser, Z. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4833-08.2008 · Cited by 382 · see citing works
An essential role for orexins in emergence from general anesthesia
Kelz, M. B., Sun, Y., Chen, J., Cheng Meng, Q., Moore, J. T., Veasey, S. C., Dixon, S., Thornton, M., Funato, H., & Yanagisawa, M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707146105 · Cited by 341 · see citing works
Mutation of a new sodium channel gene, Scn8a, in the mouse mutant ‘motor endplate disease’
Burgess, D. L., Kohrman, D. C., Galt, J., Plummer, N. W., Jones, J. M., Spear, B. T., & Meisler, M. H. (1995) · Nature Genetics · doi:10.1038/ng0895-461 · Cited by 307 · see citing works
Self-citationMolecular Identity of Dendritic Voltage-Gated Sodium Channels
Lőrincz, A., & Nusser, Z. (2010) · Science · doi:10.1126/science.1187958 · Cited by 297 · see citing works
Vazey, E. M., & Aston-Jones, G. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1310025111 · Cited by 279 · see citing works
A novel, abundant sodium channel expressed in neurons and glia
Schaller, K., Krzemien, D., Yarowsky, P., Krueger, B., & Caldwell, J. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-05-03231.1995 · Cited by 231 · see citing works
Friedman, E. B., Sun, Y., Moore, J. T., Hung, H.-T., Meng, Q. C., Perera, P., Joiner, W. J., Thomas, S. A., Eckenhoff, R. G., Sehgal, A., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011903 · Cited by 218 · see citing works
Maurice, N., Tkatch, T., Meisler, M. H., Sprunger, L. K., & Surmeier, D. J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-07-02268.2001 · Cited by 214 · see citing works
Self-citationTheta activity in the waking EEG is a marker of sleep propensity in the rat
Vyazovskiy, V. V., & Tobler, I. (2005) · Brain Research · doi:10.1016/j.brainres.2005.05.022 · Cited by 210 · see citing works
Role of Axonal NaV1.6 Sodium Channels in Action Potential Initiation of CA1 Pyramidal Neurons
Royeck, M., Horstmann, M., Remy, S., Reitze, M., Yaari, Y., & Beck, H. (2008) · Journal of Neurophysiology · doi:10.1152/jn.90332.2008 · Cited by 204 · see citing works
Slow-wave activity saturation and thalamocortical isolation during propofol anesthesia in humans
Ní Mhuircheartaigh, R., Warnaby, C., Rogers, R., Jbabdi, S., & Tracey, I. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3006007 · Cited by 202 · see citing works
Methylphenidate Actively Induces Emergence from General Anesthesia
Solt, K., Cotten, J. F., Cimenser, A., Wong, K. F. K., Chemali, J. J., & Brown, E. N. (2011) · Anesthesiology · doi:10.1097/aln.0b013e31822e92e5 · Cited by 176 · see citing works
Rehberg, B., Xiao, Y.-H., & Duch, D. S. (1996) · Anesthesiology · doi:10.1097/00000542-199605000-00025 · Cited by 162 · see citing works
O’Brien, J. E., & Meisler, M. H. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00213 · Cited by 158 · see citing works
Self-citationNaturally Occurring Variability in Anesthetic Potency Among Inbred Mouse Strains
Sonner, J. M., Gong, D., & Eger, E. I. (2000) · Anesthesia & Analgesia · doi:10.1097/00000539-200009000-00042 · Cited by 144 · see citing works
Does Epidural Anesthesia Have General Anesthetic Effects?
Hodgson, P. S. A., Liu, S. S., & Gras, T. W. (1999) · Anesthesiology · doi:10.1097/00000542-199912000-00021 · Cited by 141 · see citing works
Mutation Detection in the and Alleles of the Sodium Channel
Kohrman, D. C., Harris, J. B., & Meisler, M. H. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.29.17576 · Cited by 140 · see citing works
Self-citationSCNM1, a Putative RNA Splicing Factor That Modifies Disease Severity in Mice
Buchner, D. A., Trudeau, M., & Meisler, M. H. (2003) · Science · doi:10.1126/science.1086187 · Cited by 137 · see citing works
Self-citationPapale, L. A., Beyer, B., Jones, J. M., Sharkey, L. M., Tufik, S., Epstein, M., Letts, V. A., Meisler, M. H., Frankel, W. N., & Escayg, A. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp081 · Cited by 127 · see citing works
Self-citationRecurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy
Wagnon, J. L., & Meisler, M. H. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00104 · Cited by 124 · see citing works
Self-citationNav1.6 Sodium Channels Are Critical to Pacemaking and Fast Spiking in Globus Pallidus Neurons
Mercer, J. N., Chan, C. S., Tkatch, T., Held, J. E., & Surmeier, D. J. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3430-07.2007 · Cited by 119 · see citing works
Tung, A., Szafran, M. J., Bluhm, B., & Mendelson, W. B. (2002) · Anesthesiology · doi:10.1097/00000542-200210000-00024 · Cited by 112 · see citing works
Mangia, A. L., Pirini, M., & Cappello, A. (2014) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2014.00601 · Cited by 107 · see citing works
Naturally Occurring Variability in Anesthetic Potency Among Inbred Mouse Strains
Sonner, J. M., Gong, D., & Eger, E. I. (2000) · Anesthesia & Analgesia · doi:10.1213/00000539-200009000-00042 · Cited by 105 · see citing works
Kearney, J. A. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.22.2765 · Cited by 104 · see citing works
Sonner, J. M., Gong, D., Li, J., Eger, E. I., & Laster, M. J. (1999) · Anesthesia & Analgesia · doi:10.1097/00000539-199910000-00039 · Cited by 100 · see citing works
Sonner, J. M., Gong, D., Li, J., Eger, E. I., & Laster, M. J. (1999) · Anesthesia & Analgesia · doi:10.1213/00000539-199910000-00039 · Cited by 100 · see citing works
Joiner, W. J., Friedman, E. B., Hung, H.-T., Koh, K., Sowcik, M., Sehgal, A., & Kelz, M. B. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003605 · Cited by 82 · see citing works
Raju, S. G., Barber, A. F., LeBard, D. N., Klein, M. L., & Carnevale, V. (2013) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1003090 · Cited by 79 · see citing works
Sodium Currents in Mesencephalic Trigeminal Neurons From Nav1.6 Null Mice
Enomoto, A., Han, J. M., Hsiao, C., & Chandler, S. H. (2007) · Journal of Neurophysiology · doi:10.1152/jn.00292.2007 · Cited by 78 · see citing works
Effects of Alcohols and Anesthetics on Recombinant Voltage-Gated Na+ Channels
Shiraishi, M., & Harris, R. A. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.064063 · Cited by 77 · see citing works
Persistent Nav1.6 current at axon initial segments tunes spike timing of cerebellar granule cells
Osorio, N., Cathala, L., Meisler, M. H., Crest, M., Magistretti, J., & Delmas, P. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.183798 · Cited by 75 · see citing works
Self-citationPal, D., Lipinski, W. J., Walker, A. J., Turner, A. M., & Mashour, G. A. (2011) · Anesthesiology · doi:10.1097/aln.0b013e318204e064 · Cited by 71 · see citing works
Self-citationSodium channels as targets for volatile anesthetics
Herold, K. F., & Hemmings Jr., H. C. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00050 · Cited by 70 · see citing works
Comparative Effects of Halogenated Inhaled Anesthetics on Voltage-gated Na+Channel Function
Ouyang, W., Herold, K. F., & Hemmings, H. C. (2009) · Anesthesiology · doi:10.1097/aln.0b013e318197941e · Cited by 69 · see citing works
Barber, A. F., Carnevale, V., Klein, M. L., Eckenhoff, R. G., & Covarrubias, M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405768111 · Cited by 60 · see citing works
Noujaim, S. F., Kaur, K., Milstein, M. L., Jones, J. M., Furspan, P., Jiang, D. D., Auerbach, D. S., Herron, T. J., Meisler, M. H., & Jalife, J. (2011) · The FASEB Journal · doi:10.1096/fj.10-179770 · Cited by 57 · see citing works
Self-citationEvidence for a direct role of the disease modifier SCNM1 in splicing
Howell, V. M., Jones, J. M., Bergren, S. K., Li, L., Billi, A. C., Avenarius, M. R., & Meisler, M. H. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm206 · Cited by 41 · see citing works
Self-citationVanini, G., Nemanis, K., Baghdoyan, H. A., & Lydic, R. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12571 · Cited by 41 · see citing works
Interfaces of Sleep and Anesthesia
Mashour, G. A., & Pal, D. (2012) · Anesthesiology Clinics · doi:10.1016/j.anclin.2012.05.003 · Cited by 26 · see citing works
Self-citationOliva, M., McGarr, T. C., Beyer, B. J., Gazina, E. V., Kaplan, D. I., Cordeiro, L., Thomas, E. A., Dib‐Hajj, S. D., Waxman, S. G., Frankel, W. N., et al. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.03.007 · Cited by 24 · see citing works
Bidirectional modulation of isoflurane potency by intrathecal tetrodotoxin and veratridine in rats
Zhang, Y., Guzinski, M., Eger, E. I., Laster, M. J., Sharma, M. L., Harris, R. A., & Hemmings, H. C. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00583.x · Cited by 20 · see citing works
Pal, D., Walton, M. E., Lipinski, W. J., et al. (2011) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e31823ede22 · Cited by 20 · see citing works
Self-citationPersistent Nav1.6 current at axon initial segments tunes spike timing of cerebellar granule cells
Osorio, N., Cathala, L., Meisler, M. H., Crest, M., Magistretti, J., & Delmas, P. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.183798 · Cited by 20 · see citing works
Self-citationYokoyama, T., Minami, K., Sudo, Y., et al. (2011) · Journal of Anesthesia · doi:10.1007/s00540-011-1167-7 · Cited by 17 · see citing works
Impairment of hippocampal long-term potentiation by Alzheimer amyloid ?-peptides
Chen, Q.-S., Kagan, B. L., Hirakura, Y., & Xie, C.-W. (2000) · Journal of Neuroscience Research · doi:10.1002/(sici)1097-4547(20000401)60:1
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The Biology of General Anesthesia from Paramecium to Primate
Kelz, M. B., & Mashour, G. A. (2019) · Current Biology · doi:10.1016/j.cub.2019.09.071 · Cited by 151 · see citing works
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- Authors
- Pal, D., Jones, J. M., Wisidagamage, S., Meisler, M. H., & Mashour, G. A.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Mashour, George A.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-08-07
- Volume
- 10
- Issue
- 8
- Pages
- e0134960
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4529172
- OpenAlex
- W1925159137
- Cited by
- 17
- References
- 52
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 3
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- University of Michigan
- National Institutes of Health (NIH-R01)
- National Institute of General Medical Sciences (R01GM098578)
- National Institute of Neurological Disorders and Stroke (R01_NS34509, R01NS034509)
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Keywords
- Nav1.6, voltage-gated sodium channels, general anesthesia, volatile anesthetics, isoflurane, sevoflurane, anesthetic sensitivity, loss of righting reflex, loss of consciousness, arousal, neuronal excitability, mouse model
- MeSH terms
- Sevoflurane, Anesthesia, Anesthesia Recovery Period, Anesthetics, Animals, Electroencephalography, Isoflurane, Methyl Ethers, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutation, Theta Rhythm, Volatilization, Wakefulness, NAV1.6 Voltage-Gated Sodium Channel
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