It is proposed to investigate, on a molecular scale, whether nerve block by general anesthetics is a consequence of a multi-mechanistic mode of anesthetic action. Single sodium channels from the central nervous system will be used to infer the extent of any simultaneous involvement of several, and different anesthetic interactions: hydrogen bonding, bilayer thickness and surface tension, interfacial potentials and membrane fluidity, etc. Sodium channels from canine forebrain synaptosomes will be incorporated into lipid bilayer membranes following procedures first described by Krueger et al. (1983). Currents through individual sodium channels will be examined in the presence of general anesthetic agents with systematically varied molecular structure. The composition and the physico-chemical properties of lipid bilayer membranes will be varied, such that it should be possible to estimate the extent to which the membrane environment, and particularly the anesthetic modified bilayer, can influence sodium channel function. Halogenated ethers and alcohol derivatives will be examined in order to establish whether the ability of an anesthetic molecule to form hydrogen bonds plays an important role in the spectrum of anesthetic interactions. Anesthetic responses of the central nervous system sodium channels will be compared with those of previously studied sodium channels from the peripheral nervous system. The comparisons will establish the extent to which the extensive data base regarding anesthetic actions on peripheral sodium channels is applicable to CNS sodium channels. It should thus become possible to determine whether different sodium channels vary in their anesthetic responses. Information will likewise be gained on the influence of an anesthetic-modified membrane environment on sodium channel function. The proposed studies will consequently address the question of the relative importance of direct interactions between membrane proteins and anesthetics as opposed to indirect interactions mediated via the lipid bilayer environment.
Showing the most recent 10 out of 17 publications
