Alamethicin, monazomycin, or EIM induce electrical excitability in lipid bilayers. The voltage-dependent gating displays all the characteristics observed in excitable cells and its basic features can be quantitatively described by the Hodgkin-Huxley equations.A common molecular mechanism of membrane excitation has been postulated.It assumes that in the absence of an electrical field the channel-forming molecules lie at the surface of the membrane. An applied potential tilts them from the surface into the hydrocarbon region of the bilayer. Once in this position the molecules diffuse laterally and form aggregates which act as channels for the flow of ions.ellipsoid with t w o glutamic residues at one end, and a metal ion in four-o r five-fold coordination with peptide carbonyl oxygens at the other. An applied field pulls the cationic end through the membrane t o the other side, while the glutamic residues hold the other end attached t o the original surface. The molecules now span the membrane and aggregate, forming oligomeric channels in which most of the peptide carbonyls face toward the center, and the methyl groups outward. Monomers and dimers do not conduct and an individual channel can have different conductance values depending on the number of monomers in the aggregate and the resulting channel diameter. A quantitative description of this process matches observed gating kinetics, gating currents, and the single channel conductance increments. Without additional assumptions, inactivation follows directly from the aggregation process because with proper rate constants, the average degree of polymerization and therefore number of open channels goes through a maximum in time.In the case of alamethicin we assume that the molecule forms an elongatedThe model may also apply t o the excitation process of higher cells.

Summary.The concept of a channel that builds up from subunit molecules by way of aggregation can provide the framework for a unified description of electrical excitability in cell and model membranes at the micro-and macrokinetic level. Monte Carlo simulations of the microkinetics of a subunit channel predict two extreme kinds of gating behavior. Depending on the reaction parameters, a simulation can result either in single-step open-closed microkinetics, as elucuidated by noise analysis of excitable cell membranes, or in records resembling the multi-step conductance bursts that are measured in lipid bilayers modified by alamethicin. Numerical calculations of the voltage-clamp macrokinetics for the two cases reveal that the set of parameters that produces nerve-and muscle-like fluctuations gives Hodgkin-Huxley-type time courses, while the set that results in alamethicin-like fluctuation behavior gives alamethicin-like macrokinetics. The macrokinetic behavior is generated by summing microkinetic simulations for the nerve and the alamethicin case.

Special voltage-clamp pulse protocols are given that make differential predictions for the kinetics of models based on a simple sequential, simple cyclic, and an aggregation scheme. Detailed kinetic time-courses for the discriminating pulse protocols are numerically derived from the differential equation system that describes the aggregation model.

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