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At least 397 records · Page 22Linked to original sources
PubMed1972

Appearance of acetylcholine receptors during differentiation of a myogenic cell line.

Acquisition of acetylcholine receptors during differentiation of a clonal myoblast cell line was monitored with a neurotoxin isolated from venom of the Indian Cobra Naja naja. Toxin bound specifically and reversibly to acetylcholine receptors of the differentiated cells. Specificity of the binding reaction was assayed by measurement of the ability of various cholinergic agonists and antagonists to compete with neurotoxin for its binding site. The rate of toxin binding paralleled the rate of inactivation of functional acetylcholine receptors, as measured by iontophoretic application of acetylcholine. Bound toxin was released from the cells with a half-life of about 7 hr. This release was not associated with a decrease in the total number of toxin-binding sites. A slow hyperpolarizing response to acetylcholine seen in myoblasts was insensitive to toxin; the appearance of toxin-binding sites parallels the appearance of fused fibers during differentiation of the muscle cells in tissue culture.

Acetylcholine↗
PubMed1972

Acetylcholine receptors of muscle grown in vitro.

[(125)I]Monoiodo- and [(125)I]diiodo-alpha-bungarotoxin were synthesized and shown to bind specifically to the acetylcholine receptor of cultured embryonic chick- and rat-muscle cells. The pharmacologic properties of the receptor of cultured embryonic chick muscle resembled those of the nicotinic acetylcholine receptor of adult vertebrate muscle. Autoradiography of muscle cells labeled with toxin showed that acetylcholine receptors were distributed over the entire cell surface. In addition, discrete areas with a high receptor concentration were found.

Acetylcholine↗
PubMed1975

Regulation of binding properties of the nicotinic receptor protein by cholinergic ligands in membrane fragments from Torpedo marmorata.

Exposure of receptor-rich membrane fragments from Torpedo marmorata to carbamylcholine causes a slow (half-time of 5--10 min) and reversible change of properties of the cholinergic receptor protein manifested by a decrease of the initial rate of Naja nigricollis alpha-[3H]toxin binding in the presence of carbamylcholine. This change corresponds to a 5- to 20-fold increase of affinity for carbamylcholine. Other agonists, acetylcholine, phenyltrimethylammonium, show the same effect but not the antagonists d-tubocurarine and flaxedil. Decamethonium and hexamethonium show little, if any, agonistic effect in vitro on the same membrane fragments but cause the affinity change. This regulatory property can be lost after aging of the preparation of membrane fragments. Since the affinity increase progresses with a similar time course as the decrease of amplitude of the permeability response consecutive to agonist preincubation, it is proposed that, in the membrane at rest, the receptor protein is present under a state of low affinity for agonists and that the reversible stabilization by the agonists of a high affinity state corresponds to the "pharmacological desensitization" of the system as predicted by one of the models of Katz and Thesleff.

Acetylcholine↗
PubMed1975

Relaxation measurements on the acetylcholine receptor.

In Electrophorus electroplaques, the agonist-induced postsynaptic conductance depends on membrane potential. During steady exposure to agonists, after a voltage step the conductance relaxes on a millisecond time scale, exponentially approaching a new equilibrium value. The relaxation rate constant k is an instantaneous function of voltage, insensitive to the past or present conductance. Two components sum to form k. A concentration-sensitive component increases linearly with agonist concentration and decreases during desensitization or exposure to curare. Thus this component reflects the average frequency at which acetylcholine receptors are opening. The voltage-sensitive component, obtained by extrapolating k to zero agonist concentration, increases at more positive potentials. For acetylcholine, the voltage-sensitive component equals the rate constant for the exponential decay of postsynaptic currents; it thus seems to be the closing rate for active receptors. The voltage-sensitive component has the relative amplitudes acetylcholine less than carbamoylcholine less than decamethonium, and for each agonist equals the closing rate determined from "noise" measurements at neuromuscular junctions. The kinetic data explain several aspects of the steady-state conductance induced by agonists, but shed no light on apparent cooperative effects.

Acetylcholine↗
PubMed1978

Decamethonium both opens and blocks endplate channels.

Miniature endplate currents, endplate current fluctuations ("membrane noise"), and voltage-jump current relaxations were studied in voltage-clamped frog muscle fibers during decamethonium action. All three types of experiments revealed two kinetic processes controlling the opening of endplate channels, one that reflects agonist action and another that reflects local anesthetic-like blocking activity. The kinetic constants for these two steps were evaluated from measurements of the fast and slow time constants as a function of decamethonium concentration. At -130 mV membrane potential and 13 degrees, the mean open time of decamethonium-activated channels is 2.8 msec. The forward and backward rate constants for channel blocking are 1.7 X 10(7) M-1 sec-1 and 10(3) sec-1. The voltage dependencies of the channel lifetime and of the blocking equilibrium are similar to those seen with pure agonists and local anesthetics, respectively.

Animals↗
PubMed1993

Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase.

Binding sites of Torpedo acetylcholinesterase (EC 3.1.1.7) for quaternary ligands were investigated by x-ray crystallography and photoaffinity labeling. Crystal structures of complexes with ligands were determined at 2.8-A resolution. In a complex with edrophonium, and quaternary nitrogen of the ligand interacts with the indole of Trp-84, and its m-hydroxyl displays bifurcated hydrogen bonding to two members of the catalytic triad, Ser-200 and His-440. In a complex with tacrine, the acridine is stacked against the indole of Trp-84. The bisquaternary ligand decamethonium is oriented along the narrow gorge leading to the active site; one quaternary group is apposed to the indole of Trp-84 and the other to that of Trp-279, near the top of the gorge. The only major conformational difference between the three complexes is in the orientation of the phenyl ring of Phe-330. In the decamethonium complex it lies parallel to the surface of the gorge; in the other two complexes it is positioned to make contact with the bound ligand. This close interaction was confirmed by photoaffinity labelling by the photosensitive probe 3H-labeled p-(N,N-dimethylamino)benzenediazonium fluoroborate, which labeled, predominantly, Phe-330 within the active site. Labeling of Trp-279 was also observed. One mole of label is incorporated per mole of AcChoEase inactivated, indicating that labeling of Trp-279 and that of Phe-330 are mutually exclusive. The structural and chemical data, together, show the important role of aromatic groups as binding sites for quaternary ligands, and they provide complementary evidence assigning Trp-84 and Phe-330 to the "anionic" subsite of the active site and Trp-279 to the "peripheral" anionic site.

Acetylcholine↗
PubMed1975

Ionic properties of the acetylcholine receptor in cultured rat myotubes.

The acetylcholine reversal potential (Er) of cultured rat myotubes is -3mV. When activated, the receptor is permeable to K+ and Na+, but not to Cl- ions. Measurement of Er in Tris+-substituted, Na-free medium also indicated a permeability to Tris+ ions. Unlike adult frog muscle the magnitude of Er was insensitive to change in external Ca++ (up to 30 mM) or to changes in external pH (between 6.4 and 8.9). The equivalent circuit equation describing the electrical circuit composed of two parallel ionic batteries (EK and ENa) and their respective conductances (gK and gNa), which has been generally useful in describing the Er of adult rat and frog muscle, could also be applied to rat myotubes when Er was measured over a wide range of external Na+ concentrations. The equivalent circuit equation could not be applied to myotubes bathed in media of different external K+ concentrations. In this case, the Er was more closely described by the Goldman constant field equation. Under certain circumstances, it is known that the receptor in adult rat and frog muscle can be induced to reversibly shift from behavior described by the equivalent circuit equation to that described by the Goldman equation. Attempts to similarly manipulate the responses of cultured rat myotubes were unsussessful. These trials included a reduction in temperature (15 degress C), partial alpha-bungarotoxin blodkade, and activation of responses with the cholinergic agonist, decamethonium.

Animals↗
PubMed1987

Characterization of the basolateral membrane conductance of Necturus urinary bladder.

Necturus urinary bladders stripped of serosal muscle and connective tissue were impaled through their basolateral membranes with microelectrodes in experiments that permitted rapid changes in the ion composition of the serosal solution. The transepithelial electrical properties exhibited a marked seasonal variation that could be attributed to variations in the conductance of the shunt pathway, apical membrane selectivity, and basolateral Na+ transport. In contrast, the passive electrical properties of the basolateral membrane remained constant throughout the year. The apparent transference numbers (Ti) of the basolateral membrane for K+ and Cl- were determined from the effect on the basolateral membrane equivalent electromotive force of a sudden increase in the serosal K+ concentration from 2.5 to 50 mM/liter or a decrease in the Cl- concentration from 101 to 10 mM/liter. TK and TCl were 0.71 +/- 0.05 and 0.04 +/- 0.01, respectively. The basolateral K+ conductance could be blocked by Ba2+ (0.5 mM), Cs+ (10 mM), or Rb+ (10 mM), but was unaffected by 3,4-diaminopyridine (100 microM), decamethonium (100 microM), or tetraethylammonium (10 mM). We conclude that a highly selective K+ conductance dominates the electrical properties of the basolateral membrane and that this conductance is different from those found in nerve and muscle membranes.

4-Aminopyridine↗
PubMed2002

Molecular conformation-activity relationship of decamethonium congeners.

BACKGROUND: Of the polymethylene bismethonium congeners (C5-C12 and C18), decamethonium (C10) is the most potent neuromuscular blocking agent. We tested the hypothesis that these congeners act as straight molecules and will not bend easily in spite of the flexible connecting chain between the methonium heads. For congeners higher than C10, we also hypothesized that the relative difficulty with which the molecules to bend to conform to the interonium distance of C10 proportionately reduces their neuromuscular blocking potency. METHODS: Each congener was modelled and subjected to computer searches for representative low-energy molecular conformers. The conformation-potency relationship of the congeners was examined. RESULTS: For all congeners, we found that the lowest energy conformer (the 'global minimum') has a straight-chain conformation. Reduction of the interonium distance (by bending) incurs a steep energy penalty linearly related to the distance reduced. The global minimum of C10 has an interonium distance of 14.03 A and a total molecular length of 20.10 A. For other congeners, the interonium distance differential from that of C10 and the energy penalty required to conform to the interonium distance of C10 (where applicable) correlate with the reported logarithmic (mmol kg(-1)) dose requirement for neuromuscular block. CONCLUSIONS: The C10 congeners strongly prefer a straight conformation. Their molecular length and resistance to bending is key to their neuromuscular blocking potency. A molecular length of approximately 20 A should best fit the space available to neuromuscular blocking agents between the two receptive sites of the endplate acetylcholine receptor.

Decamethonium Compounds↗
PubMed1990

Acetylcholine receptor-mediated membrane current in oocytes injected with Electrophorus electricus mRNA: analyses of nicotine, succinylcholine, and decamethonium responses on the basis of the minimal model.

Nicotinic acetylcholine receptor was synthesized in Xenopus oocytes after injection of the mRNA purified from Electrophorus electricus electroplax. Nicotine, succinylcholine, and decamethonium (agonist)-elicited membrane currents in the injected oocytes were measured electrophysiologically by the voltage-clamping method. The following four different measurements were made to establish the relationship between the agonist concentration and the membrane current: 1) the agonist-induced membrane current before desensitization, 2) the agonist-induced membrane current after desensitization equilibrium, 3) the fraction of the active form of the receptors after desensitization equilibrium, 4) the rate of recovery of desensitized receptors upon removal of the agonist. These results were analyzed on the basis of the minimal model proposed from receptor-mediated ion translocation measurements. The equilibrium and rate constants of the model were evaluated for nicotine, succinylcholine, and decamethonium, and could explain the observed electrical responses in the injected oocyte, i.e. the characteristics of the receptor response caused by these agonists.

Animals↗