INTERACTION OF INHALED AGENTS WITH PROTEINS

Almost all investigators agree that the ultimate action of inhaled anesthetics is on specific neuronal membrane proteins that permit the translocation of ions during membrane excitation. Most believe this occurs by a direct binding of anesthetics to membrane channels, although definitive evidence for direct binding at the atomic level is not yet available. Because of the complexity involved in searching for specific anesthetic binding sites in proteins of whole brain or brain homogenate, attempts have been made to simplify this search by examining the interaction of anesthetics with isolated proteins.

Soluble Proteins

Using x-ray crystallography, distinct anesthetic binding sites have been identified in several soluble proteins, including hemoglobin, myoglobin, and albumin.^{[88] [127] [128]} Three high-affinity halothane binding sites have been identified on human serum albumin.^[129] These discrete binding sites for halothane are preformed amphiphilic pockets on the protein that are capable of binding the natural fatty acid ligands, and the binding of halothane to albumin causes little or no change in structure.^[129]

The interaction of inhaled anesthetics with soluble enzymes may be reflected indirectly by changes in enzyme activity. Many enzymes, including several glycolytic enzymes and serum cholinesterase, are resistant to even saturated solutions of volatile agents. However, other soluble enzymes are highly sensitive to clinical anesthetic concentrations. The purified firefly luciferase enzyme combines with its substrate luciferin to produce a photon of light, and a variety of inhaled anesthetics (at about 1.0 MAC) inhibit the activity (i.e., light intensity) of this enzyme by competing with luciferin.^[130] However, because luciferin has no anesthetic properties, luciferase is unlikely to represent a good model of the site of anesthetic action.^[131]