Molecular aspects of electrical excitation in lipid bilayers and cell membranes.
Several compounds of fungal or bacterial origin (EIM, alamethicin, monazomycin, DJ400B) can be incorporated into planar lipid bilayers where they form molecular channels and generate voltage-dependent ion conductances. When studied by voltage clamp, the kinetic and steady-state characteristics of these conductance changes are in every respect identical to those found in excitable cell membranes, and their major aspects can be quantitatively described by the Hodgkin-Huxley equations. Thus, the steady-state conductance is an expotential function of the membrane potential, the conductance rises with a sigmoid time course and decays exponentially, and the time constants of the conductance changes go through a maximum as a function of the potential. The conductances also show inactivation as seen in the sodium channels of nerve and the potassium channels of muscle. In addition, there appear for particular pulsing sequences certain kinetic transients that cannot be accounted for by the Hodgkin-Huxley equations but are also seen in identical form in nerve. Because the kinetics are identical in all excitable cell membranes and in these bilayers, it is likely that, in spite of the diverse chemical nature of the channel-forming molecules in the bilayers and the widely differing ion selectivities in the cellular systems, the mechanism by which the membrane opens and closes for the flow of ions is essentially the same in all cases. The kinetic data imply that a cooperative process is involved in the gating action. In principle, two different concepts could account for the kinetics--one involving an intramolecular configurational change within a complex permanent channel, the other, the assembly of a channel through the voltage-dependent aggregation of monomeric channel precursors. In the bilayers the high-order dependence of the steady-state conductance and of the gating time constants on the concentration of the channel formers suggests an aggregation mechanism in which the gating involves the voltage-induced insertion of all or part of the channel-forming molecules from the membrane surface into the hydrocarbon region and their subsequent aggregation into open channels by lateral diffusion. The mathematical description of this two-step insertion-aggregation mechanism accounts quantitatively for the entire conductancb-voltage kinetics including inactivation and other kinetic features which deviate from the Hodgkin-Huxley kinetics in the sense that the rate constants of the changes are dependent not only on the membrane potential but also on the value of the conductance and on time. The proposed mechanism is also in agreement with single-channel data for alamethicin which suggest that both the insertion and the aggregation rate constants are voltage-dependent...
D000408:Alamethicin / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D004553:Electric Conductivity; D004558:Electric Stimulation; D007700:Kinetics; D008433:Mathematics; D008564:Membrane Potentials / Q000187:drug effects; D008567:Membranes, Artificial; D008954:Models, Biological; D008961:Models, Structural; D008968:Molecular Conformation; D009424:Nervous System Physiological Phenomena
D008567:Membranes, Artificial; D000408:Alamethicin