1. Single channel currents through acetylcholine receptor channels (ACh channels) were recorded at chronically denervated frog muscle extrajunctional membranes in the absence and presence of the lidocaine derivatives QX-222 and QX-314. 2. The current wave forms due to the opening and closing of single ACh channels (activated by suberyldicholine) normally are square pulses. These single pulses appear to be chopped into bursts of much shorter pulses, when the drug QX-222 is present in addition to the agonist. 3. The mean duration of the bursts is comparable to or longer than the normal channel open time, and increases with increasing drug concentration. 4. The duration of the short pulses within a burst decreases with increasing drug concentration. 5. It is concluded that drug molecules reversibly block open end-plate channels and that the flickering within a burst represents this fast, repeatedly occurring reaction. 6. The voltage dependence of the reaction rates involved, suggested that the site of the blocking reaction is in the centre of the membrane, probably inside the ionic channel.

Local anaesthetics transiently block currents through single acetylcholine-receptor channels.

Site-directed mutagenesis and expression in Xenopus oocytes were used to study acetylcholine receptors in which serine residues (i) were replaced by alanines (alpha, delta subunits) or (ii) replaced a phenylalanine (beta subunit) at a postulated polar site within the M2 transmembrane helix. As the number of serines decreased, there were decreases in the residence time and consequently the equilibrium binding affinity of QX-222, a quaternary ammonium anesthetic derivative thought to bind within the open channel. Receptors with three serine-to-alanine mutations also displayed a selective decrease in outward single-channel currents. Both the direction of this rectification and the voltage dependence of QX-222 blockade suggest that the residues mutated are within the aqueous pore of the receptor and near its cytoplasmic (inner) surface.

http://science.sciencemag.org/content/sci/242/4885/1578.full.pdf

Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor.

The major brain nicotinic acetylcholine receptor is assembled from two subunits termed alpha 4 and n alpha 1. When expressed in Xenopus oocytes, these subunits reconstitute a functional acetylcholine receptor that is inhibited by progesterone levels similar to those found in serum. In this report, we show that the steroid interacts with a site located on the extracellular part of the protein, thus confirming that inhibition by progesterone is not due to a nonspecific perturbation of the membrane bilayer or to the activation of second messengers. Because inhibition by progesterone does not require the presence of agonist, is voltage-independent, and does not alter receptor desensitization, we conclude that the steroid is not an open channel blocker. In addition, we show that progesterone is not a competitive inhibitor but may interact with the acetylcholine binding site and that its effect is independent of the ionic permeability of the receptor.

/pdf/progesterone-modulates-a-neuronal-nicotinic-acetylcholine-2ziyhtq4k7.pdf

Progesterone Modulates a Neuronal Nicotinic Acetylcholine Receptor

Multiple sites of action for noncompetitive blockers on acetylcholine receptor rich membrane fragments from Torpedo marmorata

1. In the absence of procaine the end-plate conductance evoked by suberyldicholine increases exponentially to a new level following a step hyperpolarization. In the presence of procaine the suberyldicholine-evoked conductance first rapidly decreases and then slowly increases following a hyperpolarizing step. The fast relaxation has a time constant of approximately 1 msec, and the slow relaxation a time constant of 10-150 msec.2. The existence and sign of these two relaxations is predicted by a sequential model in which procaine enters and blocks open but not closed end-plate channels. The concentration dependence of the fast and slow relaxation time constants agrees well with the predictions of this model, and allows the apparent dissociation constant for binding of procaine within the open channel to be estimated at about 20 muM at -80 mV membrane potential.3. This apparent binding constant is voltage sensitive. It decreases e-fold for 50 mV hyperpolarization, suggesting that the procaine binding site is electrically half way through the channel.4. Procaine concentrations comparable to the dissociation constant for binding to open channels strongly depress the equilibrium current evoked by low suberyldicholine concentrations. This finding is not in accord with the sequential model.5. A cyclic model in which procaine binds to both closed and open channels explains well the equilibrium observations. The affinity of procaine for closed channels is similar to its affinity for open channels, and is also increased by hyperpolarization. This model also fits well the kinetic observations, if it is assumed that blocked channels open and close much more slowly than unblocked channels.6. The concentration dependence of the relaxation amplitudes disagrees with the predictions of the sequential model, but agrees well with the predictions of the cyclic model.7. No other model appears to explain the various observations as economically as the cyclic channel blocking model. If the model is correct the ;gate' controlling the end-plate channel must be in the inner half of the membrane.

Voltage jump analysis of procaine action at frog end-plate.

Xylocaine and its derivatives act specifically at the neuromuscular junction within the concentration range 0.05 to 2.0 mM. The charged form is the active form of the drugs. There is no correlation between "local anesthetic" activity and effect at the junction. Like d-tubocurarine, these drugs have little or no effect on quantum content, acetylcholinesterase activity, or the passive impedance of the muscle fiber. Yet they produce end plate potentials characterized by a brief, early component and a late, greatly prolonged component, as does procaine. Analysis of these changes in time course suggests that the drugs have little or no effect before receptors are activated by acetylcholine, but cause a decreased and often greatly prolonged response. Clear structure-activity relations indicate that the receptor to which the drugs bind to produce the prolonged response can be the receptor for acetylcholine. Comparison of the effects of the drugs on the end plate potential and on the response to iontophoretically applied acetylcholine also shows that the effects of Xylocaine depend on the time course of receptor activation and are quite different from the effects of d-tubocurarine.

https://rupress.org/jgp/article-pdf/52/1/144/1244331/144.pdf

Alteration by Xylocaine (Lidocaine) and Its Derivatives of the Time Course of the End Plate Potential

A kinetic scheme postulating the rapid formation of a partially active acetylcholine-receptor-drug complex from Xylocaine (or a derivative) and the active acetylcholine-receptor complex can account for the effects of Xylocaine and its derivatives at the neuromuscular junction. Transmembrane currents generated by an analogue computer programmed according to the scheme can exactly match end plate currents produced by nerve stimulation in the presence of the drugs. The scheme also accounts for the qualitatively different effects of the drugs on the end plate potential and on responses to iontophoretically applied acetylcholine. The analysis presented is consistent with very rapid reactions between acetylcholine and receptors, characterized by rate coefficients in the range 104 to 106 sec-1. It is based on the hypothesis that the activation of receptors by acetylcholine changes the structure of the receptors and thus their affinity for Xylocaine. The analysis does not require pharmacological separability of sodium and potassium conductances during the end plate current.

https://rupress.org/jgp/article-pdf/52/1/162/1244362/162.pdf

A Kinetic Model for the Action of Xylocaine on Receptors for Acetylcholine

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Alteration by Xylocaine (Lidocaine) and Its Derivatives of the Time Course of the End Plate Potential

A Kinetic Model for the Action of Xylocaine on Receptors for Acetylcholine