Lipid Ion Channels

The interpretation electrical phenomena in biomembranes is usually based on the assumption that the experimentally found discrete ion conduction events are due to a particular class of proteins called ion channels while the lipid membrane is considered being an inert electrical insulator. The particular protein structure is thought to be related to ion specificity, specific recognition of drugs by receptors and to macroscopic phenomena as nerve pulse propagation. However, lipid membranes in their chain melting regime are known to be highly permeable to ions, water and small molecules, and are therefore not always inert. In voltage-clamp experiments one finds quantized conduction events through protein-free membranes in their melting regime similar to or even undistinguishable from those attributed to proteins. This constitutes a conceptual problem for the interpretation of electrophysiological data obtained from biological membrane preparations. Here, we review the experimental evidence for lipid ion channels, their properties and the physical chemistry underlying their creation. We introduce into the thermodynamic theory of membrane fluctuations from which the lipid channels originate. Furthermore, we demonstrate how the appearance of lipid channels can be influenced by the alteration of the thermodynamic variables (temperature, pressure, tension, chemical potentials) in a coherent description that is free of parameters. This description leads to pores that display dwell times closely coupled to the fluctuation lifetime via the fluctuation-dissipation theorem. Drugs as anesthetics and neurotransmitters are shown to influence the channel likelihood and their lifetimes in a predictable manner. We also discuss the role of proteins in influencing the likelihood of lipid channel formation.Comment: Revie

Linear nonequilibrium thermodynamics of reversible periodic processes and chemical oscillations

Onsager's phenomenological equations successfully describe irreversible thermodynamic processes. They assume a symmetric coupling matrix between thermodynamic fluxes and forces. It is easily shown that the antisymmetric part of a coupling matrix does not contribute to dissipation. Therefore, entropy production is exclusively governed by the symmetric matrix even in the presence of antisymmetric terms. In this work we focus on the antisymmetric contributions which describe isentropic oscillations and well-defined equations of motion. The formalism contains variables that are equivalent to momenta, and coefficients that are analogous to an inertial mass. We apply this formalism to simple problems such as an oscillating piston and the oscillation in an electrical LC-circuit. We show that isentropic oscillations are possible even close to equilibrium in the linear limit and one does not require far-from equilibrium situations. One can extend this formalism to other pairs of variables, including chemical systems with oscillations. In isentropic thermodynamic systems all extensive and intensive variables including temperature can display oscillations reminiscent of adiabatic waves.Comment: 11 pages, 5 figure

Lipid ion channels and the role of proteins

Synthetic lipid membranes in the absence of proteins can display quantized conduction events for ions that are virtually indistinguishable from those of protein channel. By indistinguishable we mean that one cannot decide based on the current trace alone whether conductance events originate from a membrane, which does or does not contain channel proteins. Additional evidence is required to distinguish between the two cases, and it is not always certain that such evidence can be provided. The phenomenological similarities are striking and span a wide range of phenomena: The typical conductances are of equal order and both lifetime distributions and current histograms are similar. One finds conduction bursts, flickering, and multistep-conductance. Lipid channels can be gated by voltage, and can be blocked by drugs. They respond to changes in lateral membrane tension and temperature. Thus, they behave like voltage-gated, temperature-gated and mechano-sensitive protein channels, or like receptors. Lipid channels are remarkably under-appreciated. However, the similarity between lipid and protein channels poses an eminent problem for the interpretation of protein channel data. For instance, the Hodgkin-Huxley theory for nerve pulse conduction requires a selective mechanism for the conduction of sodium and potassium ions. To this end, the lipid membrane must act both as a capacitor and as an insulator. Non-selective ion conductance by mechanisms other than the gated protein-channels challenges the proposed mechanism for pulse propagation. ... Some important questions arise: Are lipid and protein channels similar due a common mechanism, or are these similarities fortuitous? Is it possible that both phenomena are different aspects of the same phenomenon? Are lipid and protein channels different at all? ... (abbreviated)Comment: 10 pages, 10 figures - accepted by 'Accounts of Chemical Research

The important consequences of the reversible heat production in nerves and the adiabaticity of the action potential

It has long been known that there is no measurable heat production associated with the nerve pulse. Rather, one finds that heat production is biphasic, and a heat release during the first phase of the action potential is followed by the reabsorption of a similar amount of heat during the second phase. We review the long history the measurement of heat production in nerves and provide a new analysis of these findings focusing on the thermodynamics of adiabatic and isentropic processes. We begin by considering adiabatic oscillations in gases, waves in layers, oscillations of springs and the reversible (or irreversible) charging and discharging of capacitors. We then apply these ideas to the heat signature of nerve pulses. Finally, we compare the temperature changes expected from the Hodgkin-Huxley model and the soliton theory for nerves. We demonstrate that heat production in nerves cannot be explained as an irreversible charging and discharging of a membrane capacitor as it is proposed in the Hodgkin-Huxley model. Instead, we conclude that it is consistent with an adiabatic pulse. However, if the nerve pulse is adiabatic, completely different physics is required to explain its features. Membrane processes must then be reversible and resemble the oscillation of springs more than resembling "a burning fuse of gunpowder" (quote A. L. Hodgkin). Theories acknowledging the adiabatic nature of the nerve pulse have recently been discussed by various authors. It forms the central core of the soliton model, which considers the nerve pulse as a localized sound pulse.Comment: 17 pages, 14 figure

The thermodynamics of general and local anesthesia

General anesthetics are known to cause depression of the freezing point of transitions in biomembranes. This is a consequence of ideal mixing of the anesthetic drugs in the membrane fluid phase and exclusion from the solid phase. Such a generic law provides physical justification of the famous Meyer-Overton rule. We show here that general anesthetics, barbiturates and local anesthetics all display the same effect on melting transitions. Their effect is reversed by hydrostatic pressure. Thus, the thermodynamic behavior of local anesthetics is very similar to that of general anesthetics. We present a detailed thermodynamic analysis of heat capacity profiles of membranes in the presence of anesthetics. This analysis is able to describe experimentally observed calorimetric profiles and permits prediction of the anesthetic features of arbitrary molecules. In addition, we discuss the thermodynamic origin of the cutoff-effect of long-chain alcohols and the additivity of the effect of general and local anesthetics.Comment: 12 pages, 9 figures, 1 tabl

Voltage Gated Lipid Ion Channels

Synthetic lipid membranes can display channel-like ion conduction events even in the absence of proteins. We show here that these events are voltage-gated with a quadratic voltage dependence as expected from electrostatic theory of capacitors. To this end, we recorded channel traces and current histograms in patch-experiments on lipid membranes. We derived a theoretical current-voltage relationship for pores in lipid membranes that describes the experimental data very well when assuming an asymmetric membrane. We determined the equilibrium constant between closed and open state and the open probability as a function of voltage. The voltage-dependence of the lipid pores is found comparable to that of protein channels. Lifetime distributions of open and closed events indicate that the channel open distribution does not follow exponential statistics but rather power law behavior for long open times

The free energy of biomembrane and nerve excitation and the role of anesthetics

In the electromechanical theory of nerve stimulation, the nerve impulse consists of a traveling region of solid membrane in a liquid environment. Therefore, the free energy necessary to stimulate a pulse is directly related to the free energy difference necessary to induce a phase transition in the nerve membrane. It is a function of temperature and pressure, and it is sensitively dependent on the presence of anesthetics which lower melting transitions. We investigate the free energy difference of solid and liquid membrane phases under the influence of anesthetics. We calculate stimulus-response curves of electromechanical pulses and compare them to measured stimulus-response profiles in lobster and earthworm axons. We also compare them to stimulus-response experiments on human median nerve and frog sciatic nerve published in the literature.Comment: 10 pages, 6 figure

Periodic solutions and refractory periods in the soliton theory for nerves and the locust femoral nerve

Close to melting transitions it is possible to propagate solitary electromechanical pulses which reflect many of the experimental features of the nerve pulse including mechanical dislocations and reversible heat production. Here we show that one also obtains the possibility of periodic pulse generation when the boundary condition for the nerve is the conservation of the overall length of the nerve. This condition generates an undershoot beneath the baseline (`hyperpolarization') and a `refractory period', i.e., a minimum distance between pulses. In this paper, we outline the theory for periodic solutions to the wave equation and compare these results to action potentials from the femoral nerve of the locust (locusta migratoria). In particular, we describe the frequently occurring minimum-distance doublet pulses seen in these neurons and compare them to the periodic pulse solutions.Comment: 10 pages, 6 Figure