吸入麻酔薬はなぜ効くのか?作用メカニズムの一端を解明 ～標的分子の1つとして1型リアノジン受容体を特定～

2025-06-04 科学技術振興機構,東京大学,久留米大学

図 1 カルシウム放出の検出実験概要図とイソフルランによる RyR1 の活性化(A)各リアノジン受容体による小胞体からのカルシウム放出を検出する実験系の概要図。(B)イソフルランが RyR1 を選択的に活性化することが分かる(平均値±標準誤差、n=4)。

<関連情報>

• https://www.jst.go.jp/pr/announce/20250604/index.html
• https://www.jst.go.jp/pr/announce/20250604/pdf/20250604.pdf
• https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003172

イソフルランは1型リアノジン受容体を活性化し、マウスに麻酔を誘導する Isoflurane activates the type 1 ryanodine receptor to induce anesthesia in mice

Hiroyuki J. Kanaya,Ken Kuwajima,Yuko Ito,Yuta Shinohara,Yohei Okubo,Shinnosuke Shiono,Fumiya Tatsuki,Rei-ichiro Ohno,Hideki Ukai,Maki Ukai-Tadenuma,Kenta Sumiyama,Hiroshi Fujishima,Rikuhiro G. Yamada, [ … ],Hiroki R. Ueda
PLOS Biology  Published: June 3, 2025
DOI:https://doi.org/10.1371/journal.pbio.3003172

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 (GABA_ARs) 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.