New study points out how universal anesthesia can make mice fall asleep

A new study sheds light on how isoflurane, a widely used inhaled anesthetic, works in the molecular layer, a confusing mystery for scientists for decades.

The researchers found that this common anesthetic directly activates the type 1 ryanodine receptor (RYR1), a protein that is critical to intracellular calcium release. This discovery, published on June 3, 2025, more clearly describes the way anesthesia is induced, and the findings of this study also suggest new ways to develop drugs that may lead to sedative conditions.

Uncover the mystery of anesthesia

Inhaled anesthetics have been the cornerstone of medical procedures since the 1840s, but their exact mechanism of action remains surprisingly complex. Although previous studies have identified several targets, such as type A receptor A (GABAARS) and two-well domain K+ (K2P) channels, the entire situation of how these compounds cause unconscious and painful states is incomplete. The RYR1 protein is known for its role in malignant high temperatures (a severe reaction to certain anesthetics), a suspicious suspect, but the direct contact was not confirmed until now.

“It was previously unsure whether inhaled anesthetics interact directly with RYR1,” the research team shared. Their work clearly shows that isoflurane, as well as other inhaled anesthetics such as Sevoflurane and Halothane, directly activate wild-type RYR1.

Key findings for RYR1 activation

The researchers used a systematic approach to examine the RYR isoforms of each mammal. Their tests in cell lines show that isoflurane specifically triggers calcium release in RYR1-expressing cells and at concentrations related to clinical use. For example, the EC50 of isoflurane on RyR1 is 203 μm, which is a clinically relevant concentration (approximately 0.7 MAC or minimum alveolar concentration).

Among the important findings of the study:

• Selective activation: Isoflurane and Sevoflurane mainly activate RyR1, with minimal impact on RyR2 and RyR3.
• Key binding sites identified: By systematically changing individual amino acids, the team pointed out specific amino acid residue M4000, which is crucial for RYR1’s response to isoflurane. Changing this single residue largely negates the effect of anesthesia.
• Resistance to anesthesia: Mice designed to have mutant forms of RyR1, especially the M4000F variant, have a loss of anti-corrected reflex (LORR) upon exposure to isoflurane. This strongly suggests a direct link between RYR1 activation and the anesthetic effects of active animals.
• New sedative potential: The discovery of new RYR1 agonists, which have the same binding site as isoflurane, resulting in the sedation of mice. This opens up exciting possibilities for future drug development.

Effects on future sedation and anesthesia

A new understanding of the action of isoflurane through RYR1 is a critical step. The exact molecular targets of anesthetics have been elusive for years, making it challenging to develop new, safer, and more targeted drugs. Now, since RYR1 is identified as a functional target, the path forward seems to be clearer.

“We propose that isoflurane directly activate RYR1, and that this activation is related to its anesthesia/sedation effects,” the authors said. Will this new insight lead to tailored side effects, even a deeper understanding of malignant hyperthermia sedatives? Only time can prove it, but this study undoubtedly provides a compelling new direction for medical science.

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