Since their anesthetic effects were discovered about 180 years ago, anesthetic inhalation was used for general anesthesia in surgery. However, the mechanism of their anesthetic has not yet been completely revealed. Previous studies have shown that inhalation anesthetically exerts their anesthetic effects by acting on multiple proteins, but the presence of unknown target molecules has also been suggested.
In rare cases, patients with abnormal Ryanodine 1 (RYR1) (RYR1 mutations) are known to be at higher risk of malignant hyperthermia, which can be caused by anesthetics. However, the immediate molecular interaction between inhaled anesthetic and RYR1 has not been clearly proven and the relationship between RYR1 and anesthetic effects was also unknown.
In the present study, a research team led by Professor Hiroki Ueda at the Postgraduate School of Medicine, University of Tokyo, found that the RYR1, which is a calcium liberalization channel, causes general anesthesia with the target molecule.
The research team initially confirmed that isoflorane and other inhaled anesthetics activated RYR1 and stimulate calcium release from the endoplasmic network. The amino acid residues in RYR1 which play an important role in the activation caused by isoflorane have been identified and assessed the position of isofluranium. In addition, the research team created a genetically modified mouse (Knock-in mouse; expressed by the RYR1 mutator that does not respond to isoflora. When Knock-in mice were exposed to isoflorane, they showed a partially reduced sensitivity to anesthesia compared to normal mice.
In addition, the new compounds aimed at the supposed isofluranium commitment were identified by the detection of the silicon union and found to have apparent results in mice. These results indicate that RYR1 is a functional target of isofluranium directly related to its anesthetic properties.
This research reveals an aspect of the molecular mechanism of inhaled anesthetic used for general anesthesia. This is a new finding, as previous studies have not proven the relationship between RYR1 and anesthetic effects on mammals. A more detailed understanding of the mechanism of action of anesthetic could lead to the development of better anesthetic and treatment methods.
The results of this study were published in the online edition of the American Scientific Journal Biology plos On June 3, 2025 (EDT).
This result was achieved in the Biological Timing Ueda project, a research field of Investigative Research on Advanced Technology (ERATO) by the Japan Science and Technology Service (JST). In the context of this project, JST seeks the “biology of human understanding systems” using the rate of sleep-loss as a model system and aims to understand information about “biological time”, which transcends molecules to individual people living in society.
Source:
Magazine report:
Kanaya, hj, et al. (2025). Isoflorane activates the type 1 Ryanodine receptor to cause anesthesia in mice. Biology plos. doi.org/10.1371/journal.pbio.3003172.
