DESPITE almost a century of research, the mechanism of anaesthesia rem
ains obscure and there is still no agreement on the location of the si
te(s) of action1-7. Because the potencies of general anaesthetics incr
ease in proportion to their solubility in olive oil, this led to a con
sensus that the site is within the cell membrane 8-10. This led to the
ories that lipid bilayer perturbation was the primary event, which was
then transmitted to a membrane protein11. But at the concentrations u
sed clinically, such perturbations are small3. A plausible site would
be in or on ion channels at the synapse, where a number of modulatory
effects have been described6. A possible location for such a site woul
d be at the protein-lipid interface5,12,13. We report here that anaest
hetics inhibit protein kinase C, a key component in signal transductio
n. The potency is a linear function of the octanol-water partition coe
fficient (the Meyer-Overton rule of anaesthesia). The effect was obtai
ned in a lipid-free assay, implicating a hydrophobic site in the prote
in, supporting the contention that a (membrane) protein may be a targe
t for anaesthetic interactions14-17. In a lipid-dependent assay, a pot
ential role of lipids in the protein-site model was demonstrated. The
inhibition was absent in the isolated catalytic domain, suggesting tha
t the site of inhibition is on the regulatory subunit, which is unique
to protein kinase C.