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R U Muller

Publications and source records attributed to R U Muller.

47 records · Page 3Linked to original sources
PubMed1982

Monazomycin-induced single channels. I. Characterization of the elementary conductance events.

Monazomycin (a positively charged, polyene-like antibiotic) induces voltage-dependent conductance changes in lipid bilayer membranes when added to one of the bathing solutions. These conductance changes have generally been attributed to the existence of channels spanning the membrane. In this article we characterize the behavior of the individual conductance events observed when adding small amounts of monazomycin to one side of a lipid bilayer. We find that there are several apparent channel types with one or sometimes two amplitudes predominating. We find further that these fairly similar amplitudes represent two different states of the same fundamental channel entity, presumed to be the monazomycin channel. The current-voltage characteristics of these channels are weakly hyperbolic functions of applied potential. The average lifetimes are essentially voltage independent (between 50 and 400 mV). The average channel intervals, on the other hand, can be strongly voltage dependent, and we can show that the time-averaged conductance of a membrane is proportional to the average channel frequency.

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PubMed1982

Monazomycin-induced single channels. II. Origin of the voltage dependence of the macroscopic conductance.

The voltage dependence of the conductance induced induced in thin lipid membranes by monazomycin is shown here to be caused by voltage-dependent variations in the frequency of channel openings. We also experimentally demonstrate certain interesting properties of the channel activity that are predicted by a chemical kinetic model (Muller and Peskin, 1981), which successfully describes the macroscopic conductance. We conclude that two parallel mechanisms--one autocatalytic, the other simple mass action--exist that allow monazomycin to enter (or leave) the membrane so that the monazomycin molecules can be in a position to form channels.

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PubMed1981

The kinetics of monazomycin-induced voltage-dependent conductance. I. Proof of the validity of an empirical rate equation.

Monazomycin (a positively-charged, polyene-like antibiotic) induces a strongly voltage-dependent conductance in thin lipid membranes when added to one of the bathing solutions. We show here that the kinetics of conductance changes after a step of membrane potential are only superficially similar to the kinetics of the potassium gating system of squid giant axons, in that the beginning of conductance increases are growth functions of the time, as opposed to power functions of the time. We find that the rate constant (reciprocal of the time constant) of the growth varies with the approximately 2.6 power of the monazomycin concentration. The rate constant also varies exponentially with membrane potential such that an e-fold change is associated with a 10-11 mV change of membrane potential. We show that solutions of a simple differential equation are able to reproduce the actual conductance changes almost exactly. In the accompanying paper (Muller and Peskin. 1981. J. Gen. Physiol. 78:201-229), we derive the differential equation from a molecular model and use the theoretical equation so obtained to investigate the gating current of this system and to predict an interesting form of memory.

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PubMed1981

The kinetics of monazomycin-induced voltage-dependent conductance. II. Theory and a demonstration of a form of memory.

The empirical differential equation that describes the kinetics of monazomycin-induced voltage-dependent conductance is derived using a standard chemical kinetic formulation and the assumption that monazomycin entry into and exit from the membrane is autocatalytic. The predicted form of gating currents is shown and numerical calculations for this process are made using a range of values for two unmeasured variables. A form of "memory" is then demonstrated, along with the ability of the theoretical equation to explain the nature of the memory.

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PubMed1976

Inactivation of monazomycin-induced voltage-dependent conductance in thin lipid membranes. I. Inactivation produced by long chain quaternary ammonium ions.

The voltage-dependent conductance induced in thin lipid membranes by monazomycin undergoes inactivation upon the introduction of quaternary ammonium ions (QA) having a long alkyl chain (e.g. dodecyltrimethylammonium [C12]) to the side containing monazomycin. That is, in response to a step of voltage the conductance rises to a peak and then falls to a much lower steady-state value. We demonstrate that the basis of this phenomenon is the ability of QA to pass through the stimulated membrane and bind to the opposite surface. As a consequence, the surface potential on that side becomes more positive, thus reducing the voltage across the membrane proper and turning off the monazomycin-induced conductance. Because the flux of QA through the membrane increases linearly with conductance, we believe that these ions pass through the monazomycin channels. QA permeability increases with alkyl chain length; remarkably, in spite of its much larger size, C12 is about 150 times more permeant than K+. It appears, therefore, that there is a hydrophobic region of the cahnnel that favors the alkyl chain; we propose that this region is formed by the hydrophobic faces of the monazomycin channels in lipid bilayers to QA inactivation of potassium channels in the squid giant azon, and suggest that there may be a common structural feature for the two channels. It is possible that some of the inactivation phenomena in excitable cells may arise from local field changes not measurable by the recording electrodes.

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PubMed1976

Inactivation of monazomycin-induced voltage-dependent conductance in thin lipid membranes. II. Inactivation produced by monazomycin transport through the membrane.

At sufficiently large conductances, the voltage-dependent conductance induced in thin lipid membranes by monazomycin undergoes inactivation. This is a consequence of depletion of monazomycin from the membrane solution interface, as monazomycin crosses the membrane to the opposite (trans) side from which it was added. The flux of monazomycin is directly proportional to the monazomycin-induced conductance; at a given conductance it is independent of monazomycin concentration. We conclude that when monazomycin channels break up, some or all of the molecules making up a channel are deposited on the trans side. We present a model for the monazomycin channel: approximately five molecules, each spanning the membrane with its NH3+ on the trans side and an uncharged hydrophilic (probably sugar) group anchored to the cis side, form an aqueous channel lined by--OH groups. The voltage dependence arises from the flipping by the electrical field of molecules lying parallel to the cis surface into the "spanned state;" the subsequent aggregation of these molecules into channels is, to a first approximation, voltage independent. The channel breakup that deposits monomers on the trans side involves the collapsing of the channel in such a way that the uncharged hydrophilic groups remain in contact with the water in the channel as they close the channel from behind. We also discuss the possibility that inactivation of sodium channels in nerve involves the movement from one side of the membrane to the other of the molecules (or molecule) forming the channel.

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PubMed1974

The electrostatic basis of Mg++ inhibition of transmitter release.

The inhibition by Mg(++) of stimulus-evoked transmitter release is attributed to a decrease in surface potential, Psi(0), on the outer surface of the presynaptic terminal and hence a lower surface calcium concentration, [Ca(++)](0). Data on the frog neuromuscular junction are quantitatively fit by assuming that there is a negative charge density, sigma, on the outer surface of the presynaptic terminal of 6.5 x 10(13) charges per cm(2) and that simple diffuse double layer theory is applicable. No specific binding of Mg(++) or Ca(++) is required. Without any additional assumptions, the inhibitory effect of univalent cations is also quantitatively predicted.

Acetylcholine↗
PubMed1972

Voltage-dependent conductance induced in thin lipid membranes by monazomycin.

When present in micromolar amounts on one side of phospholipid bilayer membranes, monazomycin (a positively charged, polyene-like antibiotic) induces dramatic voltage-dependent conductance effects. Voltage clamp records are very similar in shape to those obtained from the potassium conductance system of the squid axon. The steady-state conductance is proportional to the 5th power of the monazomycin concentration and increases exponentially with positive voltage (monazomycin side positive); there is an e-fold change in conductance per 4-6 mv. The major current-carrying ions are univalent cations. For a lipid having no net charge, steady-state conductance increases linearly with KCl (or NaCl) concentration and is unaffected by Ca(++) or Mg(++). The current-voltage characteristic which is normally monotonic in symmetrical salt solutions is converted by a salt gradient to one with a negative slope-conductance region, although the conductance-voltage characteristic is unaffected. A membrane treated with both monazomycin and the polyene antibiotic nystatin (which alone creates anion-selective channels) displays bistability in the presence of a salt gradient. Thus monazomycin and nystatin channels can exist in parallel. We believe that many monazomycin monomers (within the membrane) cooperate to form a multimolecular conductance channel; the voltage control of conductance arises from the electric field driving monazomycin molecules at the membrane surface into the membrane and thus affecting the number of channels that are formed.

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PubMed1972

The effect of surface charge on the voltage-dependent conductance induced in thin lipid membranes by monazomycin.

Differences in the behavior of phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) thin lipid membranes treated with monazomycin are shown to be due to the negative surface charge on PG membranes. We demonstrate that shifts of the conductance-voltage (g-V) characteristic of PG films produced by changes of univalent or divalent cation concentrations result from changes of the membrane surface potential on one or both sides. In particular, if divalent cations are added to the aqueous phase not containing monazomycin, the resulting asymmetry of the surface potentials results in an intramembrane potential difference not recordable by electrodes in the bulk phases. Nevertheless, this intramembrane potential difference is "seen" by the monazomycin, and consequently the g-V characteristic is shifted along the voltage axis. These changes are accounted for by diffuse double layer theory. Thus we find it unnecessary to invoke specific binding of Mg(++) or Ca(++) to the negative charges of PG membranes to explain the observation that concentrations of these ions some 100-fold lower than that of the univalent cation present produce large shifts of the g-V characteristic. We suggest that analogous shifts of g-V characteristics in axons produced by changes of divalent cation concentration are also best explained by diffuse double layer theory.

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