Isoflurane activates the type 1 ryanodine receptor to induce anesthesia in mice

Inhaled anesthetics were first introduced into clinical use in the 1840s. Molecular and transgenic animal studies indicate that inhaled anesthetics act through several ion channels, including γ-aminobutyric acid type A receptors (GABAARs) and two-pore domain K+ (K2P) channels, but other targets may mediate anesthetic effects. Mutations in the type 1 ryanodine receptor (RyR1), which is a calcium release channel on the endoplasmic reticulum membrane, are relevant to malignant hyperthermia, a condition that can be induced by inhaled anesthetics. However, it was previously uncertain whether inhaled anesthetics directly interact with RyR1. In our study, we demonstrated that isoflurane and other inhaled anesthetics activate wild-type RyR1. By employing systematic mutagenesis, we discovered that altering just one amino acid residue negates the response to isoflurane, thus helping us to pinpoint the potential binding site. Knock-in mice engineered to express a mutant form of RyR1 that is insensitive to isoflurane exhibited resistance to the loss of righting reflex (LORR) when exposed to isoflurane anesthesia. This observation suggests a connection between RyR1 activation and the anesthetic effects in vivo. Moreover, it was shown that RyR1 is involved in the neuronal response to isoflurane. Additionally, administering new RyR1 agonists, which share the same binding site as isoflurane, resulted in a sedation-like state in mice. We propose that isoflurane directly activates RyR1, and this activation is pertinent to its anesthetic/sedative effects.

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Journal
PLoS Biology
Published
2025-06-03
DOI
https://doi.org/10.1371/journal.pbio.3003172
Citations
1
Primary Topic
Ion channel regulation and function
Type
article
Field-Weighted Citation Impact
0.81

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Isoflurane activates the type 1 ryanodine receptor to induce anesthesia in mice

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PLoS Biology
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article

Isoflurane activates the type 1 ryanodine receptor to induce anesthesia in mice

Hiroki R. Ueda, Yuta Shinohara, Rei-ichiro Ohno, Masaki Kikuchi, Masamitsu Iino, Daisuke Tone, Hideki Ukai, Ken Kuwajima, Kenta Sumiyama, Hiroshi Fujishima, Takatsugu Hirokawa, Hiroki Kanaya, Fumiya Tatsuki, Takashi Umehara, Hiroshi Kiyonari, Rikuhiro G. Yamada, Yohei Okubo, Takashi Murayama, Maki Ukai‐Tadenuma, Shinnosuke Shiono, Yuko Ito, Koji L. Ode, Kazunori Kanemaru
article en
1 citations

Abstract

Inhaled anesthetics were first introduced into clinical use in the 1840s. Molecular and transgenic animal studies indicate that inhaled anesthetics act through several ion channels, including γ-aminobutyric acid type A receptors (GABAARs) and two-pore domain K+ (K2P) channels, but other targets may mediate anesthetic effects. Mutations in the type 1 ryanodine receptor (RyR1), which is a calcium release channel on the endoplasmic reticulum membrane, are relevant to malignant hyperthermia, a condition that can be induced by inhaled anesthetics. However, it was previously uncertain whether inhaled anesthetics directly interact with RyR1. In our study, we demonstrated that isoflurane and other inhaled anesthetics activate wild-type RyR1. By employing systematic mutagenesis, we discovered that altering just one amino acid residue negates the response to isoflurane, thus helping us to pinpoint the potential binding site. Knock-in mice engineered to express a mutant form of RyR1 that is insensitive to isoflurane exhibited resistance to the loss of righting reflex (LORR) when exposed to isoflurane anesthesia. This observation suggests a connection between RyR1 activation and the anesthetic effects in vivo. Moreover, it was shown that RyR1 is involved in the neuronal response to isoflurane. Additionally, administering new RyR1 agonists, which share the same binding site as isoflurane, resulted in a sedation-like state in mice. We propose that isoflurane directly activates RyR1, and this activation is pertinent to its anesthetic/sedative effects.

PLoS BiologyVol. 23(6)
Nihon University (JP), Kurume University (JP), University of Tsukuba (JP), Juntendo University (JP), RIKEN Center for Biosystems Dynamics Research (JP), Tsukuba Medical Center Hospital (JP), National Institute of Advanced Industrial Science and Technology (JP), The University of Tokyo (JP)
Takeda Science Foundation, Japan Agency for Medical Research and Development, Human Frontier Science Program, Ministry of Education, Culture, Sports, Science and Technology, Anthony Nolan Research Institute, Japan Society for the Promotion of Science, Japan Science and Technology Agency, RIKEN Center for Biosystems Dynamics Research
Openalex Percentile: Top 27%
Ion channel regulation and function
0.81
DOIOpen Access PDFOpenAlex
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