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Query: UNIPROT:P06889 (Mol)
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1. Using conventional two-microelectrode voltage-clamp techniques we studied the effects of inorganic mercury (HgCl2) on acetylcholine-, carbachol-, and glutamate-activated currents on Aplysia neurons. Hg2+ was applied with microperfusion. 2. Acetylcholine and carbachol activated an inward, sodium-dependent current in the anterior neurons of the pleural ganglion. The medial neurons gave a biphasic current to acetylcholine and carbachol, which was outward at resting membrane potential. The faster component was Cl- dependent and reversed at about -60 mV, while the slower component was K+ dependent and reversed at greater than -80 mV. 3. Hg2+ (0.1-10 microM) caused a dramatic increase in the acetylcholine- and carbachol-induced inward current in anterior neurons and the fast Cl- current in medial neurons. With only a 1-min preapplication of Hg2+, the acetylcholine- or carbachol-activated sodium or chloride currents were increased to 300% and the effect was only partly reversible. The threshold concentration was 0.1 microM Hg2+. 4. Contrary to the effects on sodium and chloride currents, concentrations of 0.1-10 microM Hg2+ caused a complete and irreversible blockade of K(+)-dependent acetylcholine and carbachol currents. The block of the potassium current was relatively fast and increased with time. The concentration of HgCl2 that gave a half-maximal blockade of the carbachol-activated potassium current was 0.89 microM. The chloride-dependent current elicited by glutamate on medial neurons was increased by HgCl2 as well. 5. These results suggest that actions at agonist-activated channels must be considered as contributing to mercury neurotoxicity. It is possible that the toxic actions of Hg2+ on synaptic transmission at both pre- and postsynaptic sites are important factors in the mechanism of Hg2+ toxicity.
Cell Mol Neurobiol 1994 Dec
PMID:Effect of HgCl2 on acetylcholine, carbachol, and glutamate currents of Aplysia neurons. 764 Dec 26

1. Aluminum (Al) has been implicated in neurotoxic syndromes in several conditions, including Alzheimer's disease (AD). The developmental stage of the mammalian brain most susceptible to Al was determined in rabbits systematically exposed to Al during the prenatal, postnatal, or second month or for 1 month as adults or as aged subjects. Eyeblink reflex classical conditioning showed an Al-induced learning deficit only in the adult and aged rabbits. 2. 4-Aminopyridine, which was reported to improve learning in AD subjects, attenuated the Al-induced learning deficit. 3. Conditioned eyeblink acquisition is slower in AD subjects than controls, supporting the Al-loaded rabbit as a model of some AD effects. 4. To determine if the Al-loaded rabbit modeled the AD cholinergic deficit, acetylcholine (Ach) overflow was measured in rabbit hippocampus using microdialysis. Aluminum pretreatment reduced basal and potassium-stimulated Ach overflow compared to controls. 5. Acetylcholine overflow increased as control rabbits acquired the conditioned eyeblink reflex, then subsequently decreased, although conditioned eyeblink performance continued. In contrast, Al-loaded rabbits showed a delay in conditioned eyeblink acquisition and greatly attenuated Ach overflow. The Al-induced attenuation of Ach overflow may contribute to the Al-induced learning deficit. 6. Brain Al entry was studied using microdialysis of blood, brain, and lateral ventricle. Aluminum rapidly entered the brain and lateral ventricle. Frontal cortical Al was greater than lateral ventricular Al, suggesting that Al primarily enters the brain through the cerebral microvasculature. 7. The brain/blood Al ratio was always significantly less than 1. This ratio was influenced by the Al form administered, brain site and animal species. Thus, there appears to be an active process moving Al out of brain extracellular fluid (ECF). 8. Brain and blood dialysate Ach concentrations were not different after cyanide addition to the dialysate, supporting the conclusion that an active process moves Al out of brain ECF.
Cell Mol Neurobiol 1994 Dec
PMID:Studies of aluminum neurobehavioral toxicity in the intact mammal. 764 Dec 37

1. Nicotine stimulated two Ca(2+)-dependent processes in rat frontal cortex synaptosomes: the phosphorylation of an 80-kDa protein band and the release of endogenous ACh.3 Both effects were mediated by neuronal nAChRs and coincided with depolarization of the synaptosomal plasma membrane induced by the drug. Changes in the state of phosphorylation of the 80-kDa band (presumed to contain synapsin I) were correlated with changes in the release of ACh as follows, from 2 to 4. 2. Blockade of predominant, nerve terminal P-type Ca2+ channels with omega-agatoxin-IVA, did not prevent nicotine from stimulating ACh release. In contrast, exposure to the toxin partially inhibited the release promoted by the depolarizing agent veratridine and attenuated protein phosphorylation induced by either nicotine or veratridine. Taken together, these data suggest that, upon nicotine stimulation. Ca2+ enters nerve terminals through two distinct pathways. The first, via Ca2+ channels, is necessary (but not sufficient) for both nicotine-induced phosphorylation and ACh release. The second, both necessary and sufficient for nicotine-induced phosphorylation and release, is the neuronal nAChR itself. 3. Preincubation of the synaptosomes with a subeffective concentration of nicotine inactivated both nicotine-induced ACh liberation and phosphorylation. This shows that diminished release is associated to decreased phosphorylation of the 80-kDa protein band, most likely as a consequence of nicotine-promoted nAChR desensitization. 4. Augmented ACh release and phosphorylation of the 80-kDa protein band were achieved by using the protein phosphatase inhibitor okadaic acid. However, okadaic acid did not summate with either nicotine or veratridine to increase ACh release further. This is probably because okadaic acid, as in other neurons, increases intracellular Ca2+ (Cholewinski et al., 1993), thus promoting desensitization of ACh release.
Cell Mol Neurobiol 1994 Aug
PMID:Concomitant protein phosphorylation and endogenous acetylcholine release induced by nicotine: dependency on neuronal nicotinic receptors and desensitization. 778 41

Chronic nicotine exposure in tobacco smokers or experimental animals is known to cause an increase in brain binding sites for nicotine. It has been proposed that this is an adaptive response of neurons to accumulation of chronically desensitized receptors. Acetylcholine receptors of the same (alpha 4)2(beta 2)3 subunit composition as the predominant subtype of brain nicotinic receptors with high affinity for nicotine have been expressed in Xenopus oocytes and in a permanently transfected fibroblast cell line. Chronic exposure of these cells to nicotine or another agonist is shown to result in an increase in receptor amount, indicating that nicotine-induced up-regulation reflects properties of the alpha 4 beta 2 receptor protein, rather than being an adaptive response unique to the neurons in which these receptors are normally expressed. The nicotine concentration dependence, time course, and extent of receptor up-regulation are similar to those reported for receptors in brain. Up-regulation does not appear to require ion flow through the ion channel, because it is also caused by mecamylamine, which blocks the ion channel, and because after prolonged exposure to nicotine most receptors become permanently unable to open their channels in response to nicotine binding. The noncompetitive antagonist mecamylamine blocks open channels more effectively, and so it is more effective at blocking channels in the presence of nicotine. Mecamylamine and nicotine are also synergistic in causing receptor up-regulation. Ligands that cause up-regulation appear to induce a conformation of the receptor that is removed from the surface and degraded more slowly.
Mol Pharmacol 1994 Sep
PMID:Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. 793 34

1. Three cyclic diterpenoids isolated from gorgonians of the Eunicea genus and characterized as eupalmerin acetate (EUAC), 12,13-bisepieupalmerin (BEEP), and eunicin (EUNI) were found to be pharmacologically active on the nicotinic acetylcholine receptor (AChR). 2. The receptor from the BC3H-1 muscle cell line was expressed in Xenopus laevis oocytes and studied with a two-electrode voltage clamp apparatus. 3. All three compounds reversibly inhibited ACh-induced currents, with IC50's from 6 to 35 microM. ACh dose-response curves suggested that his inhibition was noncompetitive. The cembranoids also increased the rate of receptor desensitization. 4. Radioligand-binding studies using AChR-rich membranes from Torpedo electric organ indicated that all three cembranoids inhibited high-affinity [3H]phencyclidine binding, with IC50's of 0.8, 11.6, and 63.8 microM for EUNI, EUAC, and BEEP, respectively. The cembranoids at a 100 microM concentration did not inhibit [alpha-125I]bungarotoxin binding to either membrane-bound or solubilized AChR. 5. It is concluded that these compounds act as noncompetitive inhibitors of peripheral AChR.
Cell Mol Neurobiol 1993 Apr
PMID:Diterpenoids from Caribbean gorgonians act as noncompetitive inhibitors of the nicotinic acetylcholine receptor. 810 24

Acetylcholine muscarinic m2 receptors (m2R) couple to heterotrimeric Gi proteins and activate the Ras/Raf/mitogen-activated protein kinase pathway and phosphatidylinositol 3-kinase in Rat 1a cells. In contrast to the m2R, stimulation of the acetylcholine muscarinic m1 receptor (m1R) does not activate the Ras/Raf/mitogen-activated protein kinase regulatory pathway in Rat 1a cells but rather causes a pronounced inhibition of epidermal growth factor and platelet-derived growth factor receptor activation of Raf. In Rat 1a cells, m1R stimulation of phospholipase C beta and the marked rise in intracellular calcium stimulated cyclic AMP (cAMP) synthesis, resulting in the activation of protein kinase A. Stimulation of protein kinase A inhibited Raf activation in response to growth factors. Platelet-derived growth factor receptor stimulation of phosphatidylinositol 3-kinase activity was not affected by either m1R stimulation or protein kinase A activation in response to forskolin-stimulated cAMP synthesis. GTP loading of Ras in response to growth factors was unaffected by protein kinase A activation but was partially inhibited by carbachol stimulation of the m1R. Therefore, protein kinase A action at the Ras/Raf activation interface selectively inhibited only one branch of the signal transduction network initiated by tyrosine kinases. Specific adenylyl cyclases responding to different signals, including calcium, with enhanced cAMP synthesis will regulate Raf activation in response to Ras.GTP. Taken together, the data indicate that G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase-stimulated mitogenic response pathways.
Mol Cell Biol 1994 Apr
PMID:Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity. 813 39

Neuromuscular synapses in Aplysia have been used as model systems to study peptidergic cotransmission. Here we describe neuromuscular preparations in which it has been possible to investigate the physiological consequences of peptide transmitter release in detail. In the first preparation, the release of peptide cotransmitters from identified motor neuron B15 has been shown to be sensitive to the pattern of stimulation. High frequencies and long burst durations evoke peptide release that modulates muscle contractions in a manner similar to that produced by exogenous cotransmitter. By contrast, the release of the same peptide transmitters from motor neuron B1 show little dependence on pattern. We conclude that there are no stimulation patterns that are prerequisites for peptide release. Peptide cotransmitter release from motor neuron B47 has also been studied. B47, depending on the stimulation pattern, uses either ACh, which acts as a conventional inhibitory transmitter, or ACh plus neuropeptides, which act as excitatory modulatory cotransmitters. Thus, neuropeptide cotransmitters have the capability to greatly increase synaptic plasticity at neuromuscular synapses.
Mol Neurobiol
PMID:Functional roles of peptide cotransmitters at neuromuscular synapses in Aplysia. 817 42

At least three subtypes of alpha-bungarotoxin-sensitive acetylcholine receptors (alpha Bgt-sensitive AChRs) exist in chick brain and retina. All may contain previously unknown structural subunits. One subtype contains alpha 7 subunits. Another contains alpha 8 subunits. A third contains both alpha 7 and alpha 8 subunits. In this article, we describe, for the first time, the pharmacological characterization of alpha 7 AChRs and alpha 8 AChRs immunoisolated from chick retina. Pharmacologically, the alpha 8 AChRs exhibit two classes of binding sites, the high affinity of which have higher affinity for most cholinergic ligands than do alpha 7 AChRs. These differences are most accentuated for ACh (approximately 5400-fold), decamethonium (approximately 1400-fold), 1,1,-dimethyl-4 phenylpiperazinium (approximately 200-fold), atropine (approximately 200-fold), nicotine (approximately 100-fold), and tetramethylammonium (approximately 100-fold). The alpha 8 AChR low affinity sites exhibit affinities that are similar but not identical to that of alpha 7 AChRs. Many of the pharmacological differences between the alpha 7 AChRs and alpha 8 AChRs can be attributed to the limited differences between the amino acid sequences of the N-terminal region of the alpha 7 and alpha 8 subunits because expressed alpha 7 homomers and alpha 8 homomers also exhibit these characteristic differences.
Mol Pharmacol 1993 Nov
PMID:Pharmacological characterization of alpha-bungarotoxin-sensitive acetylcholine receptors immunoisolated from chick retina: contrasting properties of alpha 7 and alpha 8 subunit-containing subtypes. 824 8

Rate control in acetylcholinesterase (AChE) involves a single anionic site whose anionic center controls rate-related biochemical and conformational changes in the E (free enzyme) and EA (acylated enzyme) conformers. Change in conformer structure and biochemistry affect binding, acylation, and hydrolysis. It is significant that the anionic-esteratic intersite distance is not altered during conformer change as E is converted to EA. In this enzyme system, cationic acetylcholine and anionic AChE are true structural, functional, and biochemical counterparts. The anionic center in the E conformer lies at the bottom of a sterically restricted, hydrophobic cleft < 8 A wide at the top and > 3 A wide at the bottom, while the anionic center in the EA conformer is relatively open. It is characterized by a decrease in the relative binding of hydrophobic cations and by an ability to bind large organic cations. Binding of acetylcholine, H+, or organic cations at the anionic site controls k2(acylation) in the E conformer and k3(hydrolysis) in the EA conformer. Acetylcholine binding forms the ES complex in which the cation maximizes k2. In the EAS complex, the cation reduces k3 and provides allosteric control. Anionic site structure and biochemistry and the effect of pH on k2 and k3 differentiates AChE from butyrylcholinesterase. This comprehensive study of kinetic and thermodynamic processes in AChE was made possible by the synthesis and/or use of families of over 30 cationic and acylation probes of known stereochemistry. They act as rulers of the E and EA conformers of AChE and provide comparative data on kinetic-based and thermodynamic-based constants. Cationic inhibitors affect decarbamylation rates in AChE and provide an additional set of comparative data related to the mechanism of substrate hydrolysis by AChE. Acridine araphanes are unique neural receptor and cholinergic enzyme probes. Their parallel plane and coplanar conformations are related to bridge length. Two parallel plane acridine araphanes are pure uncompetitive inhibitors of AChE. Scatchard plots of the binding of methylacridinium and 9-aminoacridine with the E conformer and 9-aminoacridine with the EA conformer indicate binding at a single anionic site. No ternary complex (EII or EAII) from two-site binding was detected. In AChE, nonspecific, low-level binding at surface ionic and hydrophobic areas is ubiquitous. Binding affinity differences greater than two orders of magnitude distinguish binding at the anionic site from low level binding at surface moieties. Surface binding provides environmental and stability changes in the enzyme but does not modify the fundamental biochemistry of the E and EA conformers.
Mol Pharmacol 1994 Jan
PMID:Conformers of acetylcholinesterase: a mechanism of allosteric control. 830 83

Bovine serum albumin greatly enhanced the cholinergic response mediated by neuronal nicotinic acetylcholine receptors in chick ciliary ganglion neurons. The enhancement exceeded 5-fold in some experiments (mean +/- standard error, 3.26 +/- 0.43-fold) and was rapid, was dose dependent, and occurred without changes in the unitary conductance or the mean open time of the acetylcholine receptor channel. This lack of detectable change in permeation or kinetic properties suggests that bovine serum albumin might increase acetylcholine responses by increasing the number of functional receptors. The enhancement appears to be specific to the albumin molecule, because activity could not be removed by detergent extraction, gel filtration, or dialysis. Acetylcholine responses in these cells are known to be enhanced by a cAMP-dependent mechanism that converts existing acetylcholine receptors from a nonfunctional to a functional state. We found that the enhancement by bovine serum albumin occurred without an increase in cAMP and that pretreatment with membrane-permeable cAMP analogs prevented any additional enhancement of the cholinergic response by bovine serum albumin. These observations are consistent with a cAMP-dependent modulation of the enhancement produced by bovine serum albumin or a convergence of the two enhancement mechanisms onto a single pathway.
Mol Pharmacol 1993 May
PMID:Modulation by albumin of neuronal cholinergic sensitivity. 838 92


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