The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Thalamic Microinfusion of Antibody to a Voltage-gated Potassium Channel Restores Consciousness during Anesthesia
Open accessAbstract
POTASSIUM (K) channels play a major role in regulating tissue excitability. There are at least four different types of K channels that serve slightly different functions in the nervous system, including voltage-gated (Kv), calcium-activated (KCa), inward rectifying (Kir), and 2-pore (K2P) domain background leak channels.1Many authors have suggested that K channels are involved in producing the effects of anesthesia.1–6Much recent focus has been placed on distinguishing K2P channels as possible targets of anesthetic action,6,7yet interactions with various other K channels like the Kv channels may also be important.2,3,8,9Kv channels are further divided into 12 families (Kv1–Kv12) on the basis of sequence homology and similarity to Drosophila melanogaster (i.e. , fruit-fly) genes.10In Drosophila , the Kv channel genes produce multiple versions of a particular channel and are more commonly known by historical nomenclature such as: Shaker (Kv1.1–Kv1.8), Shab (Kv2.1–Kv2.2), Shaw (Kv3.1–Kv3.4), Shal (Kv4.1–Kv4.3), and ether-a-go-go (Kv10.1–Kv10.2). The eight members of the Shaker -related K channel family (Kv1.1–Kv1.8) are involved with generating voltage-dependent outward currents that regulate action potential threshold, as well as waveform and pacemaker activity in excitable tissue. Kv channels are generally composed of tetramers of alpha subunits. When they are expressed as homomeric channels, most have “delayed rectifier” properties, and the others will exhibit fairly rapid inactivation.11The different Kv1.x family members (where x is any one of the possible eight different subunits) can coassemble into channels with mixed heteromeric alpha subunit compositions. Furthermore, Kv-beta subunits also exist and add on another layer of complex functional diversity in vivo .11The subunit composition of the Kv1 channels not only determines their gating and kinetic properties, it also dramatically affects their expression and localization.11The idea that Kv channels might play a role in anesthesia emerged from the discovery that Drosophila Shaker mutants shake their legs vigorously during ether anesthesia.12,13The Shaker mutant lacks a normal functioning Kv1.x channel, suggesting that the suppression of neural activity under ether anesthesia depends to some extent on a properly functioning Kv1.x channel. Indeed, the amount of isoflurane needed to anesthetize a Shaker mutant with a completely nonfunctioning Kv1.x channel is more than twice the dose needed to anesthetize wild-type flies.14Importantly, the changes in isoflurane doses needed to anesthetize various other Shaker mutants parallels the expected reductions in ionic currents mediated through the respective malfunctioning K channels.14In other words, the more defective the K channel (and the less current that passes through it), the greater the dose of isoflurane needed to anesthetize a particular Shaker mutant. This seems to suggest that anesthesia might work in part by hijacking the functioning of the Kv1.x channel.Recently, the unconsciousness of sleep was also linked to a voltage-dependent K channel.15Mutagenesis analysis was used to screen more than 9,000 Drosophila lines to identify those with a limited ability to sleep. Genetic analysis of these flies revealed a point mutation in a conserved domain of the Shaker gene that involves the voltage sensing portion of Kv1.2 channel.15,16Thus, for Drosophila to sleep, it appears to need current to properly flow through its Kv1.2 channels. Taken together with the earlier anesthesia work, this suggests Kv1.2 channels might be involved with mediating the effects of volatile anesthetics on consciousness.Concurrent with the developments in sleep neurophysiology, a possible role for the central medial thalamus (CMT) in contributing to the unconsciousness of anesthesia was recently identified.17Anesthetic-induced unconsciousness can be reversed with a localized and site-specific microinfusion of nicotine into the CMT of rats.17As the loss of consciousness associated with sleep and anesthesia may share overlapping neurobiological mechanisms,18–21and nicotine is known to also block various K channels,22,23including some Kv channels,24the hypothesis is raised that anesthetic effects on consciousness might involve interactions with Kv1.2 channels located, in part, in the CMT. Herein, we open the investigation into this area of research by microinfusing a Kv1.2 channel blocking antibody directly into the CMT of rats placed in an anesthetic chamber exposed to a dose of inhalational agent that is just sufficient to render them unconscious. As in the case of Drosophila Shaker mutants, which have a chronic malfunction of Kv1.x channels, the acute conduction blockade of the Kv1.2 channels in the CMT should act to rapidly increase the anesthetic dose required to keep the animals unconscious. As the dose of anesthesia will be held constant after the localized antibody microinfusion, a positive result (indicating the possible contr
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Localized infusion of KV1 channel inhibitors into the central thalamus of rodents reverses ongoing sevoflurane or desflurane anesthesia at steady-state [59, 60], arguing that these channels play an important role in establishing arousal thresholds across evolutionarily distant species.”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [59]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585
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 1,295
Alkire, M. T., Hudetz, A. G., & Tononi, G. (2008) · Science · doi:10.1126/science.1149213 · Cited by 1,245
Self-citationVan der Werf, Y. D., Witter, M. P., & Groenewegen, H. J. (2002) · Brain Research Reviews · doi:10.1016/s0165-0173(02)00181-9 · Cited by 994
Mechanisms of Actions of Inhaled Anesthetics
Campagna, J. A., Miller, K. W., & Forman, S. A. (2003) · New England Journal of Medicine · doi:10.1056/nejmra021261 · Cited by 805
Molecular and neuronal substrates for general anaesthetics
Rudolph, U., & Antkowiak, B. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1496 · Cited by 771
Gutman, G. A., Chandy, K. G., Adelman, J. P., Aiyar, J., Bayliss, D. A., Clapham, D. E., Covarriubias, M., Désir, G. V., Furuichi, K., Ganetzky, B., et al. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.4.9 · Cited by 582
The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway
Nelson, L. E., Guo, T. Z., Lu, J., Saper, C. B., Franks, N. P., & Maze, M. (2002) · Nature Neuroscience · doi:10.1038/nn913 · Cited by 568
Reduced sleep in Drosophila Shaker mutants
Cirelli, C., Bushey, D., Hill, S., Huber, R., Kreber, R. A., Ganetzky, B., & Tononi, G. (2005) · Nature · doi:10.1038/nature03486 · Cited by 474
Localization of Voltage-Gated Ion Channels IN Mammalian Brain
Trimmer, J. S., & Rhodes, K. J. (2004) · Annual Review of Physiology · doi:10.1146/annurev.physiol.66.032102.113328 · Cited by 442
Alkire, M. T., Haier, R. J., & Fallon, J. H. (2000) · Consciousness and Cognition · doi:10.1006/ccog.1999.0423 · Cited by 391
Self-citationExpression of functional potassium channels from Shaker cDNA in Xenopus oocytes
Timpe, L. C., Schwarz, T. L., Tempel, B. L., Papazian, D. M., Jan, Y. N., & Jan, L. Y. (1988) · Nature · doi:10.1038/331143a0 · Cited by 387
Molecular targets underlying general anaesthesia
Franks, N. P. (2006) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706441 · Cited by 380
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
Brainstem projections to midline and intralaminar thalamic nuclei of the rat
Krout, K. E., Belzer, R. E., & Loewy, A. D. (2002) · Journal of Comparative Neurology · doi:10.1002/cne.10236 · Cited by 328
Sonner, J. M., Antognini, J. F., Dutton, R. C., Flood, P. D., Gray, A. T., Harris, R. A., Homanics, G. E., Kendig, J. J., Orser, B. A., Raines, D. E., et al. (2003) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000081063.76651.33 · Cited by 328
A Causal Role for Brain-Derived Neurotrophic Factor in the Homeostatic Regulation of Sleep
Faraguna, U., Vyazovskiy, V. V., Nelson, A. B., Tononi, G., & Cirelli, C. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.5510-07.2008 · Cited by 300
Stereospecific Effects of Inhalational General Anesthetic Optical Isomers on Nerve Ion Channels
Franks, N. P., & Lieb, W. R. (1991) · Science · doi:10.1126/science.1925602 · Cited by 280
Sheehan, K. C. F., Lai, K. S., Dunn, G. P., Bruce, A. T., Diamond, M. S., Heutel, J. D., Dungo-Arthur, C., Carrero, J. A., White, J. M., Hertzog, P. J., et al. (2006) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2006.26.804 · Cited by 260
Sleep, Anesthesiology, and the Neurobiology of Arousal State Control
Lydic, R., & Baghdoyan, H. A. (2005) · Anesthesiology · doi:10.1097/00000542-200512000-00024 · Cited by 253
Role of endogenous sleep-wake and analgesic systems in anesthesia
Lu, J., Nelson, L. E., Franks, N., Maze, M., Chamberlin, N. L., & Saper, C. B. (2008) · Journal of Comparative Neurology · doi:10.1002/cne.21685 · Cited by 230
Two Heteromeric Kv1 Potassium Channels Differentially Regulate Action Potential Firing
Dodson, P. D., Barker, M., & Forsythe, I. D. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-16-06953.2002 · Cited by 230
Thalamic Microinjection of Nicotine Reverses Sevoflurane-induced Loss of Righting Reflex in the Rat
Alkire, M. T., McReynolds, J. R., Hahn, E. L., & Trivedi, A. N. (2007) · Anesthesiology · doi:10.1097/01.anes.0000270741.33766.24 · Cited by 228
Self-citationThe TREK K2P channels and their role in general anaesthesia and neuroprotection
Franks, N. P., & Honoré, E. (2004) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2004.09.003 · Cited by 214
Monoclonal Antibody Blockade of the Human Eag1 Potassium Channel Function Exerts Antitumor Activity
Gómez‐Varela, D., Zwick-Wallasch, E., Knötgen, H., Sánchez, A., Hettmann, T., Ossipov, D. A., Weseloh, R. M., Contreras‐Jurado, C., Rothe, M., Stühmer, W., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0107 · Cited by 200
PROJECTIONS FROM CORTEX TO CEPHALIC BRAIN STEM (RETICULAR FORMATION) IN MONKEY
French, J. D., Hernández-Pen, R., & Livingston, R. B. (1955) · Journal of Neurophysiology · doi:10.1152/jn.1955.18.1.74 · Cited by 184
Devor, M. G., & Zalkind, V. I. (2001) · Pain · doi:10.1016/s0304-3959(01)00345-1 · Cited by 176
Antibody Engineering for the Development of Therapeutic Antibodies
Kim, S. J., Park, Y.-W., & Hong, H. J. (2005) · Molecules and Cells · doi:10.1016/s1016-8478(23)25245-0 · Cited by 167
Antibodies as valuable neuroscience research tools versus reagents of mass distraction
Rhodes, K. J., & Trimmer, J. S. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2728-06.2006 · Cited by 162
Dendrotoxins: Structure-Activity Relationships and Effects on Potassium Ion Channels
Harvey, A. L., & Robertson, B. (2004) · Current Medicinal Chemistry · doi:10.2174/0929867043363820 · Cited by 159
Cellular mechanisms for preservation of timing in central auditory pathways
Trussell, L. O. (1997) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(97)80027-x · Cited by 153
Barnes‐Davies, M., Barker, M., Osmani, F., & Forsythe, I. D. (2004) · European Journal of Neuroscience · doi:10.1111/j.0953-816x.2003.03133.x · Cited by 122
Nicotine Is a Potent Blocker of the Cardiac A-Type K+Channels
Wang, H., Shi, H., Zhang, L., Pourrier, M., Yang, B., Nattel, S., & Wang, Z. (2000) · Circulation · doi:10.1161/01.cir.102.10.1165 · Cited by 121
Douglas, C. L., Vyazovskiy, V. V., Southard, T. L., Chiu, S. Y., Messing, A., Tononi, G., & Cirelli, C. (2007) · BMC Biology · doi:10.1186/1741-7007-5-42 · Cited by 115
Kues, W. A., & Wunder, F. (1992) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1992.tb00155.x · Cited by 113
Nacif-Coelho, C., Corréa-Sales, C., Chang, L. L., & Maze, M. (1994) · Anesthesiology · doi:10.1097/00000542-199412000-00029 · Cited by 110
Dringenberg, H. C., & Olmstead, M. C. (2003) · Neuroscience · doi:10.1016/s0306-4522(03)00197-0 · Cited by 109
Anesthetic-sensitive 2P Domain K+Channels
Patel, A. J., & Honoré, É. (2001) · Anesthesiology · doi:10.1097/00000542-200110000-00034 · Cited by 107
Hurst, R. S., Busch, A. E., Kavanaugh, M. P., Osborne, P. B., North, R. A., & Adelman, J. P. (1991) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)15369-8 · Cited by 92
Trout, W. E., & Kaplan, W. D. (1970) · Experimental Gerontology · doi:10.1016/0531-5565(70)90033-1 · Cited by 91
Sukhotinsky, I., Zalkind, V. I., Lu, J., Hopkins, D. A., Saper, C. B., & Devor, M. G. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05399.x · Cited by 82
Potassium channels: basic aspects, functional roles, and medical significance.
Yost, C. (1999) · Anesthesiology · doi:10.1097/00000542-199904000-00035 · Cited by 78
Characterization of gabaergic seizure regulation in the midline thalamus
Miller, J. W., & Ferrendelli, J. A. (1990) · Neuropharmacology · doi:10.1016/0028-3908(90)90026-n · Cited by 75
Yamakura, T., Lewohl, J. M., & Harris, R. A. (2001) · Anesthesiology · doi:10.1097/00000542-200107000-00025 · Cited by 71
Identification of a Median Thalamic System Regulating Seizures and Arousal
Miller, J. W., Hall, C. M., Holland, K. D., & Ferrendelli, J. A. (1989) · Epilepsia · doi:10.1111/j.1528-1157.1989.tb05331.x · Cited by 64
Mechanisms of Anesthesia: Towards Integrating Network, Cellular, and Molecular Level Modeling
Århem, P., Klement, G., & Nilsson, J. (2003) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300142 · Cited by 62
Finnegan, T. F., Chen, S.-R., & Pan, H. (2005) · Journal of Neurophysiology · doi:10.1152/jn.01004.2005 · Cited by 61
Anti-Ca 2+ channel antibody attenuates Ca 2+ currents and mimics cerebellar ataxia in vivo
Liao, Y. J., Safa, P., Chen, Y.-R., Sobel, R. A., Boyden, E. S., & Tsien, R. W. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710771105 · Cited by 56
The central medial nucleus: thalamic site of seizure regulation
Miller, J. W., & Ferrendelli, J. A. (1990) · Brain Research · doi:10.1016/0006-8993(90)90411-4 · Cited by 54
Some Neurophysiologic Aspects of Consciousness
Bogen, J. E. (1997) · Seminars in Neurology · doi:10.1055/s-2008-1040918 · Cited by 53
Ethanol selectively blocks a noninactivating K+ current expressed in Xenopus oocytes.
Covarrubias, M., & Rubin, E. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.15.6957 · Cited by 50
Franks, N. P., Lieb, W. R., & Raja, S. N. (2004) · Anesthesiology · doi:10.1097/00000542-200407000-00034 · Cited by 47
Specific Antibodies to the External Vestibule of Voltage-gated Potassium Channels Block Current
Zhou, B.-Y., Ma, W., & Huang, X. (1998) · The Journal of General Physiology · doi:10.1085/jgp.111.4.555 · Cited by 44
Homeostatic Regulation of Kv1.2 Potassium Channel Trafficking by Cyclic AMP
Connors, E. C., Ballif, B. A., & Morielli, A. D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m708875200 · Cited by 41
Analysis of anesthetic action on the potassium channels of the Shaker mutant of Drosophila
TINKLENBERG, J. A., SEGAL, I. S., TIANZHI, G., & MAZE, M. (1991) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1991.tb33884.x · Cited by 39
Direct Block of Inward Rectifier Potassium Channels by Nicotine
Wang, H., Yang, B., Zhang, L., Xu, D., & Wang, Z. (2000) · Toxicology and Applied Pharmacology · doi:10.1006/taap.2000.8896 · Cited by 35
Halothane acts on many potassium channels, including a minimal potassium channel
Zorn, L. J., Kulkarni, R. S., Anantharam, V., Bayley, H., & Treistman, S. N. (1993) · Neuroscience Letters · doi:10.1016/0304-3940(93)90145-b · Cited by 32
Fu, X. W., Nurse, C. A., & Cutz, E. (2007) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00098.2007 · Cited by 26
Antibody-based Validation of CNS Ion Channel Drug Targets
Rhodes, K. J., & Trimmer, J. S. (2008) · The Journal of General Physiology · doi:10.1085/jgp.200709926 · Cited by 25
Knockout of the gene encoding the K2P channel KCNK7 does not alter volatile anesthetic sensitivity
Yost, C. S., Oh, I., Eger, E. I., & Sonner, J. M. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.05.010 · Cited by 22
2P Domain K+ Channels: Novel Pharmacological Targets for Volatile General Anesthetics
Patel, A. J., & Honoré, É. (2003) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-9280-2_2 · Cited by 15
Shimada, H., Uta, D., Nabekura, J., & Yoshimura, M. (2007) · Brain Research · doi:10.1016/j.brainres.2007.01.016 · Cited by 9
Unexpected awakening from anaesthesia after hyperstimulation of the medial thalamus in the rat
Stienen, P. J., van Oostrom, H., & Hellebrekers, L. J. (2008) · British Journal of Anaesthesia · doi:10.1093/bja/aen110 · Cited by 3
Cited by
Sorted by citations
Boveroux, P., Vanhaudenhuyse, A., Bruno, M.-A., Noirhomme, Q., Lauwick, S., Luxen, A., Degueldre, C., Plenevaux, A., Schnakers, C., Phillips, C., et al. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181f697f5 · Cited by 630
Taylor, N. E., Van Dort, C. J., Kenny, J. D., Pei, J., Guidera, J. A., Vlasov, K. Y., Lee, J. T., Boyden, E. S., Brown, E. N., & Solt, K. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614340113 · Cited by 269
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
Tasserie, J., Uhrig, L., Sitt, J. D., Manasova, D., Dupont, M., Dehaene, S., & Jarraya, B. (2022) · Science Advances · doi:10.1126/sciadv.abl5547 · Cited by 171
The Neural Circuits Underlying General Anesthesia and Sleep
Moody, O. A., Zhang, E. R., Vincent, K. F., Kato, R., Melonakos, E. D., Nehs, C. J., & Solt, K. (2021) · Anesthesia & Analgesia · doi:10.1213/ane.0000000000005361 · Cited by 176
Metadata
- Authors
- Alkire, M. T., Asher, C. D., Franciscus, A. M., & Hahn, E. L.
- Affiliations
- Associate Professor in Residence, Department of Anesthesiology and Perioperative Care and Fellow, the Center for the Neurobiology of Learning and Memory.
- Medical Student.
- University of California, Irvine (US)
- Staff Research Associate, Department of Anesthesiology.
- Venue
- Anesthesiology
- Published
- 2009-04-01
- Volume
- 110
- Issue
- 4
- Pages
- 766-773
- ISSN
- 0003-3022 (ISSN-L)
- OpenAlex
- W2090397682
- Cited by
- 105
- References
- 63
- Citations by year
- 2025: 4 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 7 · 2015: 8 · 2014: 4 · 2013: 6 · 2012: 8
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Anesthesiology (publishedVersion)
- PubMed (publishedVersion)
- 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
- voltage-gated potassium channels, anesthesia, consciousness, microinfusion, thalamus, Shakers, Shaw, Kv1.1, Kv1.2, Kv1.3 potassium channel, Kv1.4, Kv1.5, Kv1.6
- MeSH terms
- Sevoflurane, Desflurane, Anesthesia, Inhalation, Animals, Antibodies, Arousal, Consciousness, Cytoskeletal Proteins, Drosophila, Isoflurane, Male, Methyl Ethers, Microinjections, Nerve Tissue Proteins, Thalamic Nuclei, Potassium Channels, Rats, Sprague-Dawley, Anesthetics, Inhalation, Rats, Kv1.2 Potassium Channel
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
