Inhaled anesthetics are essential for general anesthesia during surgical procedures, but the mechanisms by which they work are not yet fully understood. Previous research has identified multiple intracellular proteins that inhaled anesthetics act upon to exert their effects, but it is believed that other unknown target molecules involved in the mechanism of action also exist.
A research team led by Professor Hiroki Ueda of the Graduate School of Medicine at the University of Tokyo has now demonstrated for the first time in mouse experiments that inhaled anesthetics activate an intracellular protein called "type 1 ryanodine receptor (RyR1)" and that this target molecule is involved in the induction of general anesthesia.
The research team first confirmed in experiments using cell lines that inhaled anesthetics such as isoflurane activate RyR1 and promote calcium release from the endoplasmic reticulum, an intracellular structure. Next, they created receptors that fused RyR1, which responds to isoflurane, with type 2 ryanodine receptors, which do not respond to isoflurane, in various ratios to identify the amino acid sites of RyR1 that play an important role in isoflurane-induced activation and estimated the binding site. Furthermore, they found that mice genetically modified to disturb the binding site showed partially reduced sensitivity to anesthesia, and that administration of novel compounds that act on the estimated binding site of isoflurane to mice had effects similar to sedation.
When mice are administered novel compounds that act on the binding site of isoflurane, effectiveness improves (right).