Inhibition of T-type calcium current in rat thalamocortical neurons by isoflurane
Open accessAbstract
Thalamocortical (TC) neurons provide the major sensory input to the mammalian somatosensory cortex. Decreased activity of these cells may be pivotal in the ability of general anesthetics to induce loss of consciousness and promote sleep (hypnosis). T-type voltage-gated calcium currents (T-currents) have a key function regulating the cellular excitability of TC neurons and previous studies have indicated that volatile general anesthetics may alter the excitability of these neurons. Using a patch-clamp technique, we investigated the mechanisms whereby isoflurane, a common volatile anesthetic, modulates isolated T-currents and T-current-dependent excitability of native TC neurons in acute brain slices of the rat. In voltage-clamp experiments, we found that isoflurane strongly inhibited peak amplitude of T-current, yielding an IC(50) of 1.1 vol-% at physiological membrane potentials. Ensuing biophysical studies demonstrated that inhibition was more prominent at depolarized membrane potentials as evidenced by hyperpolarizing shifts in channel availability curves. In current-clamp experiments we found that isoflurane decreased the rate of depolarization of low-threshold-calcium spikes (LTCSs) and consequently increased the latency of rebound spike firing at the same concentrations that inhibited isolated T-currents. This effect was mimicked by a novel selective T-channel blocker 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). In contrast, isoflurane and TTA-P2 had minimal effect on resting membrane potential and cell input resistance. We propose that the clinical properties of isoflurane may at least partly be provided by depression of thalamic T-currents.
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CaV3.1 T-channels in the thalamus are inhibited by volatile anesthetics.
“Electrophysiological recordings in the thalamus demonstrate that CaV3.1 T-channels are inhibited by volatile anesthetics [66].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [66]
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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
- Eckle, V.-S., DiGruccio, M. R., Uebele, V. N., Renger, J. J., & Todorovic, S. M.
- Affiliations
- University of Virginia Health System (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Todorovic, Slobodan M.
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 63
- Issue
- 2
- Pages
- 266-273
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC3372673
- OpenAlex
- W2032446707
- Cited by
- 31
- References
- 48
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 3 · 2014: 1 · 2013: 4
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM070726, GM070726)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- isoflurane, T-type calcium current, thalamocortical neurons, general anesthetics, neuronal excitability, low-threshold calcium spikes, channel availability, loss of consciousness, sleep induction, thalamus
- MeSH terms
- Action Potentials, Animals, Calcium, Calcium Channel Blockers, Cerebral Cortex, Dose-Response Relationship, Drug, Female, Isoflurane, Male, Membrane Potentials, Neurons, Thalamus, Rats, Sprague-Dawley, Calcium Channels, T-Type, Rats
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