The potency of most general anesthetics can be predicted by a shared physical feature, lipid solubility. This originally led to the hypothesis that anesthetics worked on the lipid membrane, and more recently has motivated investigations of the effects of anesthetics on the lipids of synthetic and biological membranes. These studies have inspired more detailed theories of general anesthetic action, each of which specifies some essential perturbation of membrane lipid (e.g. disrupting phase separations or lipid disordering). But such theories share some conspicuous weaknesses. First, the mechanism by which each lipid perturbation leads to inexcitability is vague. Second, they are not more successful at predicting potency than is bulk lipid solubility alone. Third, although these lipid-based theories generate testable predictions, very little work has been done in this area. A more mechanistic approach is to observe the effects of general anesthetics on a highly purified target structure, and relate structural changes to function. Nicotinic acetylcholine receptor-rich membranes from the electric organ of the marine ray, Torpedo can be isolated in the abundance and purity appropriate for molecular level studies. The structure of the acetylcholine receptor is known better than that of any other ion channel, and the functional properties are also known in great detail. The acetylcholine receptor has recently been used to elucidate the membrane actions of other drugs essential to modern anesthetic practice, the local anesthetics, barbiturates, and relaxants. The ability of a chemically and physically diverse group of general anesthetics (e.g. volatiles, alcohols, alkanes, inert gases, fluorinated gases, sterols, long chain alcohols and alkanes) to desensitize the receptor will be studied by radioligand (3H-ACh) binding techniques. In parallel, anesthetic effects on the bulk lipid membrane and the lipid-protein interface will be studied by spin-labeling methods. Does the ability of these structurally diverse general anesthetics and pressure to alter 3H-ACh binding parallel their ability to perturb lipid?
