Drug interactions with nerve membrane components regulating ionic permeability: action of tetrodotoxin, procaine,...

The interaction of neuroactive agents with surface membrane ionizable groups which regulate passive ionic permeability in crayfish giant axons was examined. Every ionizable membrane group was found to contribute in various degrees to regulating membranes ionic permeability. However, some membrane ionizable groups have dominant control over specific ions. Thus potassium and sodium passive permeability is predominantly activated by deprotonation of imidazole on protein and the secondary ionization of phosphatidic acid. Chloride permeability appears activated almost entirely by protonation of amino side groups on protein. The conformational state of membrane protein which regulates ionic permeability changed when the axon was potassium depolarized. The effects of tetrodotoxin, ethanol, and the amphipathic molecules procaine and pentobarbital, on the passive ionic conductances were determined. Both procaine and pentobarbital could, when charged, alter specific ionic conductances through their effects on surface double layer potentials although protein conformational changes were also involved. Studies on animals made dependent with ethanol showed an increased passive sodium conductance which further increased following ethanol withdrawal. A physical mechanism for ethanol dependency is suggested. Although the above four agents show differences in how they alter specific ionic conductances of nerve, their common mode of action, at concentrations which block the action potential, is to prevent a normal conformational change in membrane protein from occurring when nerve is depolarized.