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PubMed1987

Immunocytochemical localization of acetylcholine receptors in locust brain using auto-anti-idiotypic acetylcholine antibodies.

Auto-anti-idiotypic antibodies have been detected in antisera of rabbits immunized with an acetylcholine (ACh) conjugate. These antibodies were found to bind to ACh receptor (ACh-R) purified from different species membranes. They competed with the ACh-R antagonist alpha-bungarotoxin and some agonists such as ACh conjugate and ACh itself. They did not recognize acetylcholinesterase. Their characterization 'in vitro' suggested their employment as an immunohistological marker for ACh-R. In the locust brain, specific immunoreactivity was found in neuropils of the protocerebrum, the optic lobes, the deutocerebrum and the tritocerebrum.

Acetylcholine↗
PubMed1992

Acetylcholine synthesis is modulated by acetylcholine content of cytosolic fraction but not by that of releasable fraction.

Synthesis and release of acetylcholine (ACh) in the rat hippocampal slices were examined to clarify the mechanism of modulation of ACh synthesis. Treatment with 2-(4-phenylpiperidino)cyclohexanol (AH5183, 50 microM), an inhibitor of ACh transport from cytosol to synaptic vesicles, inhibited the increase in ACh content of the membrane-bound fraction which is readily releasable, but did not affect the cytosolic ACh content. Under these conditions, the total ACh content reached a plateau value. These results indicate that ACh synthesis is modulated by cytosolic ACh content but not by the vesicular fraction.

Acetylcholine↗
PubMed1985

Acetylcholine responses of identified neurons in Helix pomatia--I. Interactions between acetylcholine-induced and potential-dependent membrane conductances.

The influence of potential-dependent membrane conductances on amplitude and time course of acetylcholine (ACh) responses was studied. The investigations were performed on the identified neurons B1 and B3 of the buccal ganglion of Helix pomatia. The neurons B1 and B3 were depolarized by ACh. The depolarization was accompanied by a decrease of membrane resistance. An inward rectification occurring negative to the resting membrane potential (RMP) reduced the amplitude of the ACh depolarizations. An outward rectification occurring positive to the RMP consisted of two parts and ceiled the ACh responses. The early outward current reduced the amplitude and modified the time course of ACh responses. Local responses or axonal action potentials increased the amplitude of the ACh depolarizations.

Acetylcholine↗
PubMed1985

Acetylcholine responses of identified neurons in Helix pomatia--II. Pharmacological properties of acetylcholine responses.

A pharmacological separation of depolarizing and hyperpolarizing mechanisms involved in the generation of acetylcholine (ACh) depolarizations was attempted in the identified neurons B1 and B3 of the buccal ganglia of Helix pomatia. The selectivity of the drugs employed was assayed in non-identified buccal neurons in which ACh increased a hyperpolarizing Cl- conductance. Voltage clamp techniques were used. Under control conditions the depolarizing ACh currents increased non-linearly with more negative membrane potentials. The hyperpolarizing ACh currents showed a linear potential dependence. The buffer substance Tris (5 mmol/l) depressed the depolarizing ACh currents. The effect was accentuated with more negative membrane potentials. Tris failed to affect hyperpolarizing ACh responses. HEPES (5 mmol/l) did not change depolarizing or hyperpolarizing ACh responses. d-Tubocurarine (0.02-0.2 mmol/l), hexamethonium (0.5-5.0 mmol/l) and atropine (0.1 mmol/l) blocked the depolarizing and hyperpolarizing ACh responses. Arecoline (0.1 mmol/l) had neither an agonistic nor an antagonistic effect on the identified and on the non-identified neurons. It displayed an anticholinesterase activity. Anthracene-9-carbonic acid (0.5 mmol/l) depressed selectively the hyperpolarizing ACh responses. In the neurons B1 and B3 no pharmacologically separable hyperpolarizing ACh responses were detected to be superimposed on the ACh depolarizations.

Acetylcholine↗
PubMed1985

Acetylcholine responses of identified neurons in Helix pomatia--III. Ionic composition of the depolarizing currents induced by acetylcholine.

The ionic composition of the currents underlying the acetylcholine (ACh) depolarizations in the identified neurons B1 and B3 of the buccal ganglia of Helix pomatia was analysed. The equilibrium potential of the ACh responses was -2.8 +/- 0.6 mV (N = 49) and -4.0 +/- 0.7 mV (N = 79; mean +/- SEM) in the neurons B1 and B3, respectively. Replacement of NaCl in the bath solution by sucrose shifted the ACh equilibrium potential into the negative direction. A similar but less pronounced shift occurred when Ca2+ was substituted for Na+. Substitution of Cl- in the bath solution by propionate or an increase of the intracellular Cl- concentration did not affect the ACh equilibrium potential. Changes of K+ concentration in the bath between 1 and 50 mmol/l left the ACh equilibrium potential nearly unaffected when the Na+ concentration was at the control level. With a simultaneous reduction of extracellular Na+ an increase of K+ concentration shifted the ACh equilibrium potential towards more positive potentials. The findings are compatible with calculated K+ permeabilities if a K+ redistribution across the cell membrane is considered. In the neurons B1 and B3, channels operated by ACh are permeable for K+, Na+ and Ca2+, with the relative permeabilities 1.6:1.0:0.1.

Acetylcholine↗
PubMed2004

Acetylcholine-related bowel dysmotility in homozygous mutant NCX/HOX11L.1-deficient (NCX-/-) mice-evidence that acetylcholine is implicated in causing intestinal neuronal dysplasia.

BACKGROUND/PURPOSE: Homozygous mutant Ncx/Hox11L.1-deficient (Ncx-/-) mice develop mega-ileo-ceco-colon (mega-ICC) with a caliber change in the proximal colon. The authors investigated the mechanism of intestinal dysmotility in these mice. METHODS: Five-week-old Ncx-/- mice with mega ICC were compared with age-matched BDF1 control mice. Jejunum, ileum, and colon were excised from all mice and 1.0-cm-long strips of each organ, each with a resting tension of 0.5g, were suspended in an organ bath filled with Tyrode's solution at 37 degrees C and bubbled with a mixture of 95% oxygen and 5% carbon dioxide. Contractile responses to acetylcholine chloride (ACh), histamine, serotonin, and barium chloride (BaCl2) were recorded isometrically. RESULTS: For ACh, Ncx-/- mice had decreased distal colon circular muscle contraction only at lower doses and decreased distal colon longitudinal muscle contraction for all doses compared with controls (P <.05 or P <.01). In the proximal colon, Ncx-/- mice had increased circular muscle contraction only at higher doses and decreased longitudinal muscle contraction only at lower doses compared with controls (P <.01 or P <.05). ACh did not affect jejunum, and there were no significant effects on ileum. There was no response to histamine and serotonin by any part of the bowel, and the response to BaCl2 was the same for both Ncx-/- mice and controls. CONCLUSIONS: Only ACh differentially affected muscle contraction in Ncx-/- mice in the proximal and distal colon. Thus, ACh is implicated in causing the bowel dysmotility seen in Ncx-/- mice and human IND.

Acetylcholine↗
PubMed1987

Kinetics of activation of acetylcholine receptors in a mouse muscle cell line under a range of acetylcholine concentrations.

We studied, using the patch-clamp technique, the kinetics of single acetylcholine (ACh)-activated channels in a mouse muscle cell line. In the presence of high ACh concentrations we estimated the rate of channel isomerization into the open state (beta) from the dwell time between openings. Also, we obtained estimates for beta under low agonist concentrations by assuming a linear sequential model of channel activation and applying burst analysis. If the linear model is correct, then the two estimates of beta should agree since beta should be independent of ACh concentration. However, the estimates of beta obtained under low ACh concentrations were slower than those obtained independently under high ACh concentrations. The discrepancy in the estimates of beta suggests that the linear model is inadequate, but the discrepancy can be explained if open channels can close through two separate pathways. Two alternative kinetic models that can account for our data are discussed.

Acetylcholine↗
PubMed1997

Oral administration of KW-5092, a novel gastroprokinetic agent with acetylcholinesterase inhibitory and acetylcholine release enhancing activities, causes a dose-dependent increase in the blood acetylcholine content of beagle dogs.

Acetylcholine (ACh) was detected in the blood and plasma of beagle dogs using a specific, sensitive radioimmunoassay. The mean basal ACh contents in the blood and plasma of beagle dogs were 451 +/- 65 and 83.5 +/- 12.3 pg/ml (+/- SEM, n = 7), respectively, and were lower than the contents in humans reported previously by our laboratory. Oral administration of KW-5092 (10-30 mg/kg), a gastroprokinetic agent with acetylcholinesterase (AChE) inhibitory and ACh release enhancing activities, caused a dose-dependent increase in the ACh content of both the blood and plasma, as well as several behavioral side effects due to peripheral cholinergic stimulation. The size of the increase in the plasma ACh content at each dose of KW-5092 was greater than that in the blood, indicating that KW-5092 caused the increase in the blood ACh content through elevation of the plasma ACh content, by inhibition of AChE and facilitation of ACh release. These results demonstrate that the blood ACh of beagle dogs is present mainly in the blood cells and to a lesser degree in the plasma, and that KW-5092 increased the blood ACh content mainly by increasing the plasma ACh concentration.

Acetylcholine↗
PubMed1993

A high-affinity site for acetylcholine occurs close to the alpha-gamma subunit interface of Torpedo nicotinic acetylcholine receptor.

Affinity labeling techniques have been used to investigate the location of high-affinity binding sites for cholinergic agonists on the Torpedo acetylcholine receptor and the extent of overlap of these sites with those for long alpha-neurotoxins. Following reduction of the receptor by dithiothreitol, reaction with [3H]bromoacetylcholine leads to covalent incorporation into each of the two alpha subunits. At high concentrations of [3H]bromoacetylcholine (240 microM) and with prolonged incubation times (1-2 h), this labeling was not inhibited by either alpha-bungarotoxin or alpha-najatoxin. Following maximum labeling by [3H]bromoacetylcholine, no residual high binding sites for [125I]-alpha-bungarotoxin could be detected in the membrane-bound receptor, but 50% of the original sites were recovered by receptor solubilization. Since it has previously been reported that one of the two sites for alpha-bungarotoxin in the membrane-bound receptor is readily reversible but is converted to a high-affinity state by solubilization [Conti-Tronconi, B. M., Tang, F., Walgrave, S., & Gallagher, W. (1990) Biochemistry 29, 1046-1054], these results demonstrate that the covalently bound agonist inhibits the binding of alpha-bungarotoxin only to its higher affinity site in the membrane. When [3H]bromoacetylcholine labeling was carried out after reduction of the receptor by sodium borohydride rather than dithiothreitol, both alpha and gamma subunits of the receptor were labeled. Labeling of both subunits was completely inhibited if the receptor was first reduced with dithiothreitol and the alpha subunit sites were previously covalently labeled by unlabeled bromoacetylcholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1984

Desensitization of membrane-bound Torpedo acetylcholine receptor by amine noncompetitive antagonists and aliphatic alcohols: studies of [3H]acetylcholine binding and 22Na+ ion fluxes.

Measurements of the kinetics of binding of [3H]acetylcholine ([3H]AcCh) to membrane-bound nicotinic AcCh receptors from Torpedo electric tissue have been used to characterize the effects of a series of amine and alcohol noncompetitive antagonists on receptor conformational equilibria. The receptor exists in multiple, interconvertible conformations distinguished by agonist binding affinity. In the absence of cholinergic ligands, certain aromatic amines including proadifen, dimethisoquin, and lidocaine, as well as propanol and butanol, produce a dose-dependent increase in the fraction of receptors (f) in a high-affinity conformation from a value of fmax approximately 0.17 in the absence of drug to fmax approximately 0.9. Not all noncompetitive antagonists produce that same value of fmax. For histrionicotoxin (HTX), fmax approximately 0.3, and the aromatic amine adiphenine did not alter f while tetracaine actually decreased f to 0.1. The high-affinity receptor conformation stabilized by noncompetitive antagonists was characterized by (1) the rate constant (krec) for receptor reisomerization upon removal of stabilizing ligand and (2) the rate constant (kdis) for dissociation of [3H]AcCh-receptor complexes. On the basis of these criteria, the high-affinity receptor conformation stabilized by amine and alcohol noncompetitive blockers is the same as that stabilized by agonist. At 4 degrees C, krec = (2.2 +/- 0.2) X 10(-3) s-1 and kdis = 4 X 10(-2) s-1. Since HTX and adiphenine produced only a small conformational perturbation, their effects on the actions of proadifen and 2-propanol were examined. HTX and adiphenine antagonized the conformational perturbation caused by proadifen, while mixtures of HTX and 2-propanol produced additive effects. Effects of noncompetitive blockers were also assayed in terms of the inhibition of agonist-induced efflux of 22Na+ from Torpedo vesicles. Exposure to proadifen in the absence of agonist produced a reversible inhibition (desensitization) of the flux response, and recovery from desensitization occurred at the same rate as the reisomerization from the high-affinity receptor state.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1976

Dynamic properties of isolated acetylcholine receptor protein: kinetics of the binding of acetylcholine and Ca ions.

Kinetic and thermodynamic constants for elementary steps associated with the interaction of acetylcholine (AcCh) and Ca with isolated AcCh receptor from Torpedo californica have been determined by chemical relaxation spectrometry. Murexide as used as a Ca indicator to monitor changes in Ca bound to the AcCh receptor. In the presence of AcCh this technique permits an indirect monitoring of AcCh binding, because the AcCh and the Ca binding reactions are competitively coupled. A temperature-jump perturbation in the Camurexide-AcCh receptor system induces a spectrum of relaxation processes characterized by at least three relaxation times: tau1 = 5 (+/-1) msec; tau2 = 35 (+/-5) msec; and tau3 = 300 (+/-30) msec. In the presence of AcCh, the Ca relaxation spectrum is altered in a characteristic way. A formalism is developed to describe the normal mode relaxation times of the coupled reaction system in terms of total concentrations of both AcCh and receptor binding sites. The analysis also allows one to determine the stoichiometry of the reactions involved or to estimate a molecular weight of the AcCh receptor. The kinetic data suggest that the reaction of AcCh with receptor proceeds in at least two steps. The rate constant of the association of AcCh with receptor was found to be 2.4(+/-0.5) X 10(7) M-1 sec-1 at 23.5 degrees, 0.1 M NaCl, 50 mM Tris-HCl, pH 8.5. Reaction schemes consistent with the present kinetic data are discussed in terms of physiocochemical model that accounts for the rapid transient conductivity changes in excitable membranes during nerve and muscle excitation.

Acetylcholine↗
PubMed1979

Mechanism of acetylcholine release: possible involvement of presynaptic muscarinic receptors in regulation of acetylcholine release and protein phosphorylation.

Acetylcholine (AcCho) release from purely cholinergic Torpedo synaptosomes was evoked by K+ depolarization in the presence of Ca2+. Activation of muscarinic receptors, present in the synaptosomal fraction, by the agonist oxotremorine resulted in the inhibition of AcCho liberation. This inhibition was abolished by the muscarinic antagonist atropine, which by itself has no effect. These findings suggest that the muscarinic receptor, present in the electric organ of Torpedo is presynaptic and that its physiological function is to regulate AcCho release by negative feedback. The mechanism of presynaptic muscarinic inhibition was investigated by examining the effect of muscarinic ligands on synaptosomal 45Ca2+ uptake and on the level of phosphorylation of specific synaptosomal proteins. Ca2+-dependent K+ depolarization-induced synaptosomal AcCho release was accompanied by 45Ca2+ uptake and by a marked increase in the phosphorylation of a specific synaptosomal protein (band alpha) of approximately 100,000 daltons. Activation of the muscarinic receptor by the agonist oxotremorine had no detectable effect on synaptosomal 45Ca2+ uptake but resulted in the concomitant inhibition of AcCho release and of phosphorylation of band alpha. The muscarinic antagonist atropine abolished the inhibitory effect of oxotremorine both on AcCho liberation and on phosphorylation of band alpha. These findings suggest that phosphorylation of band alpha may be involved in regulation of the presynaptic processes that underly AcCho release and that activation of the muscarinic receptor by agonists may inhibit AcCho release by blocking the phosphorylation of band alpha.

Acetylcholine↗
PubMed1983

Complete mRNA coding sequence of the acetylcholine binding alpha-subunit of Torpedo marmorata acetylcholine receptor: a model for the transmembrane organization of the polypeptide chain.

A 1,350-base-pair-long cDNA clone, named p alpha-2, was isolated by hybridization to the previously characterized clone p alpha-1 and found to be specific for the alpha-subunit of the Torpedo marmorata acetylcholine receptor. The nucleotide sequences of both cDNA inserts were analyzed and the sequence of the complete coding region and part of the 5' and 3' untranslated regions of the alpha-chain mRNA was determined. The complete amino acid sequence of the alpha-chain precursor is presented and used to develop a model for the transmembrane organization of the polypeptide.

Acetylcholine↗
PubMed1985

Is an acetylcholine transport system responsible for nonquantal release of acetylcholine at the rodent myoneural junction?

Experiments were performed to investigate the effects on the spontaneous, nonquantal release of acetylcholine (AcCho) from motor nerve terminals of substances known to inhibit the AcCho transport system present in cholinergic synaptic vesicles. In mouse diaphragms, the hyperpolarization normally produced by d-tubocurarine in the endplate area of muscle fibers that had been treated by an anticholinesterase was partly or completely blocked by 2-(4-phenylpiperidino)cyclohexanol (AH5183, 0.1-1 microM), quinacrine (0.1 microM), and tetraphenylborate (1 microM). Since the sensitivity of the subsynaptic area to AcCho was not changed, the block of the hyperpolarizing action of d-tubocurarine indicated in inhibition of the spontaneous, nonquantal release of AcCho. This was confirmed in experiments on rat diaphragm using direct radioenzymatic measurement of the AcCho released into the incubation medium. The release of AcCho from the innervated diaphragm was decreased by about 50% in the presence of AH5183 (0.01-1 microM) and by 42% in the presence of quinacrine (0.1-1 microM). The AcCho released was presumably neural, since the release of AcCho from 4-day denervated diaphragms was not diminished by either AH5183 or quinacrine. The results indicate that the spontaneous release of AcCho from the motor nerve terminals is highly sensitive to low concentrations of specific inhibitors and is probably mediated by a carrier. It is proposed that spontaneous release is due to the incorporation into the membrane of the nerve terminal during exocytosis of the vesicular transport system responsible for moving AcCho into the vesicle.

Acetylcholine↗
PubMed1972

Acetylcholine receptors. Distribution and extrajunctional density in rat diaphragm after denervation correlated with acetylcholine sensitivity.

Using (125)iodine-labeled alpha-bungarotoxin (alpha-BGT-(125)I) and quantitative radioautography, we have studied the time-course of the change in acetylcholine (ACh) receptor distribution and density occurring in rat diaphragm after denervation. In innervated fibers, ACh receptors are localized at the neuromuscular junction and the extrajunctional receptor density is less than five receptors per square micrometer. The extrajunctional receptor density begins to increase between 2 and 3 days after denervation and increases approximately linearly to 1695 receptors/microm(2) at 14 days, subsequently decreasing to 529 receptors/microm(2) at 45 days. We have isolated plasma membranes from rat leg muscles at various times after denervation and find that the change in concentration of ACh receptors in the membranes measured by alpha-BGT-(125)I binding and scintillation counting follows a time-course similar to the change in ACh receptor density measured radioautographically. Furthermore, we have correlated extrajunctional ACh receptor density measured by radioautography with extrajunctional ACh sensitivity measured by iontophoretic application of ACh and intracellular recording and find that the log of ACh receptor density is related to 0.53 times the log of ACh sensitivity. These results are discussed in terms of the electrophysiological experiments on the ACh receptor and the recent, more biochemical approaches to the study of ACh receptor control and function.

Acetylcholine↗
PubMed2002

Clinical and angiographical characteristics of acetylcholine- induced spasm: relationship to dose of intracoronary injection of acetylcholine.

OBJECTIVES: The purpose of this study was to clarify clinical and angiographical characteristics of acetylcholine (ACh)-induced spasm in the right and left coronary artery. METHODS AND RESULTS: We performed 557 consecutive procedures of spasm provocation tests of ACh from January 1991 to December 2000 in patients without significant stenosis. ACh was injected in incremental doses of 20, 50 and 80 microg into the right coronary artery and in incremental doses of 20, 50 and 100 microg into the left coronary artery if spasm had not been provoked. Coronary spasm was defined as positive with more than 99% transient luminal narrowing. Proximal spasm was defined as that of segments 1, 2, 5, 6, 7 and 11 and distal spasm as that of segments 3, 4, 8, 9, 12, 13 and 14. Low-ACh-dose-induced spasms showed the clinical findings and angiographical characteristics of higher incidence of variant angina, proximal spasms, focal spasms, more ST elevation and ischemic heart disease. In contrast, angiographical characteristics of high-Ach-dose-induced spasms were distal spasms and diffuse spasms and there was less variant angina and less ST elevation. CONCLUSIONS: Lower ACh doses induced spasms more proximally and focally in the coronary artery, while higher doses of ACh provoked spasms more distally and diffusely.

Acetylcholine↗
PubMed1984

Measurement of acetylcholine turnover rate in brain: an adjunct to a simple HPLC method for choline and acetylcholine.

An existing method for measuring acetylcholine (ACh) and choline (Ch) is shown to be useful for measuring the turnover rate of ACh in mouse brain. Methyl-[3H]Ch is injected into mice. They are killed at different times by microwave irradiation and Ch and ACh extracted and separated by reverse-phase HPLC. Ch and ACh are converted to hydrogen peroxide by a post-column enzyme reaction. Hydrogen peroxide, which is directly related to the tissue content of Ch or ACh, is determined electrochemically. The fractions that correspond to the detector response for Ch and ACh are collected for the measurement of radioactivity. In this way specific radioactivities of endogenous Ch and ACh are estimated in the same sample. We used the specific radioactivity values determined by this procedure to estimate the turnover of ACh for striatum, cerebral cortex, and hippocampus of the mouse.

Acetylcholine↗
PubMed1986

Stoichiometries of acetylcholine uptake, release, and drug inhibition in Torpedo synaptic vesicles: heterogeneity in acetylcholine transport and storage.

Highly purified Torpedo electric organ synaptic vesicles form a 49 nM suspension at 1 mg protein/ml. Under active transport conditions hundreds of molecules of [3H]acetylcholine ([3H]ACh) can be accumulated per vesicle, which requires the ACh transporter to undergo multiple turnovers. The transport blocker trans-2-(4-phenylpiperidino)cyclohexanol (AH5183) has no effect on storage of endogenous ACh by vesicles. In contrast, AH5183, other blocking drugs, and nonradioactive ACh caused a rapid release of at least 30-63 molecules of newly transported [3H]ACh per vesicle. Thus AH5183 distinguishes recently transported "new" vesicular ACh from "old" endogenous ACh. l-AH5183 inhibits transport of ACh with a half-inhibitory concentration of 16 +/- 7 nM at 12 nM vesicles and 115 +/- 34 nM at 120 nM vesicles. With the assumption that AH5183 acts on a receptor in an unamplified manner about 2.7 or fewer receptors per vesicle need to be occupied to cause inhibition of ACh transport. The apparent amplification in the number of [3H]ACh molecules per vesicle that are released by AH5183 suggests that AH5183 inhibits ACh storage by an indirect mechanism that distinguishes new from old ACh.

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