New Study Pinpoints How Common Anesthetic Puts Mice to Sleep

A new study sheds light on how isoflurane, a widely used inhaled anesthetic, works at a molecular level, a mystery that has puzzled scientists for decades.

Researchers have found that this common anesthetic directly activates the type 1 ryanodine receptor (RyR1), a protein crucial for calcium release within cells. This discovery, published on June 3, 2025, offers a clearer picture of how anesthesia is induced, and remarkably, the study’s findings also suggest new avenues for developing drugs that could bring about a sedation-like state.

Unraveling the Anesthetic Mystery

Since the 1840s, inhaled anesthetics have been a cornerstone of medical procedures, yet their exact mechanisms of action have remained surprisingly complex. While previous research identified some targets, such as GABA type A receptors (GABAARs) and two-pore domain K+ (K2P) channels, the full picture of how these compounds induce a state of unconsciousness and pain relief was incomplete. The RyR1 protein, known for its role in malignant hyperthermia—a severe reaction to certain anesthetics—had been a suspect, but a direct link wasn’t confirmed until now.

“It was previously uncertain whether inhaled anesthetics directly interact with RyR1,” shared the research team. Their work definitively shows that isoflurane, along with other inhaled anesthetics like sevoflurane and halothane, directly activates wild-type RyR1.

Key Findings on RyR1 Activation

The researchers used a systematic approach, examining each mammalian RyR isoform. Their tests in cell lines revealed that isoflurane specifically triggers calcium release in cells expressing RyR1, at concentrations relevant to clinical use. For example, the EC50 for isoflurane on RyR1 was 203 μM, which is a clinically relevant concentration (approximately 0.7 MAC, or minimum alveolar concentration).

Among the study’s significant findings:

• Selective Activation: Isoflurane and sevoflurane primarily activated RyR1, with minimal effects on RyR2 and RyR3.
• Key Binding Site Identified: By systematically changing single amino acids, the team pinpointed a specific amino acid residue, M4000, as critical for RyR1’s response to isoflurane. Altering this single residue largely negated the anesthetic’s effect.
• Resistance to Anesthesia: Mice engineered to have a mutant form of RyR1, specifically the M4000F variant, were resistant to the loss of righting reflex (LORR) when exposed to isoflurane. This strongly suggests a direct link between RyR1 activation and the anesthetic effect in living animals.
• New Sedative Potential: The discovery of new RyR1 agonists, which share the same binding site as isoflurane, resulted in a sedation-like state in mice. This opens up exciting possibilities for future drug development.

Implications for Future Sedation and Anesthesia

This new understanding of isoflurane’s action through RyR1 is a pivotal step. For years, the precise molecular targets of anesthetics have remained elusive, making it challenging to develop new, safer, and more targeted drugs. Now, with RyR1 identified as a functional target, the path forward seems clearer.

“We propose that isoflurane directly activates RyR1, and this activation is pertinent to its anesthetic/sedative effects,” the authors stated. Could this new insight lead to tailored sedatives with fewer side effects, or perhaps even a deeper understanding of conditions like malignant hyperthermia? Only time will tell, but this research certainly offers a compelling new direction for medical science.