Mapping of general anaesthetic target sites provides a molecular basis for cutoff effects

A longstanding and unresolved problem in general anaesthesia is the so-called `cutoff' effect; as one ascends a homologous series of anaesthetic agents, the potencies progressively increase with anaesthetic size but then, rather suddenly, anaesthetic potency disappears^1-5. Curiously, this cutoff in potency occurs at very different points in different series. Various explanations have been offered^5,6, usually based on the notion that lipid bilayers are the primary target sites in general anaesthesia^3,4,7. However, accumulating evidence now suggests that proteins are the primary sites of action^8-14. Here we demonstrate cutoff effects for the anaesthetic inhibition of a soluble protein (firefly luciferase) which mirror those found for general anaesthesia, and we describe how the molecular architecture of the binding site accounts for the different cutoffs in the different homologous series. We show that this behaviour is a natural consequence of anaesthetics binding to an amphiphilic protein pocket of circumscribed dimensions. When general anaesthetic target sites in animals and the luciferase protein are mapped out using the fine details of the potency data, remarkable similarities are revealed. Our results thus suggest that the target sites in general anaesthesia are amphiphilic pockets on proteins.