Journal articles on the topic 'Nicotinic Acetylcholine Receptor'
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Hawkins, Brian T., Richard D. Egleton, and Thomas P. Davis. "Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 1 (July 2005): H212—H219. http://dx.doi.org/10.1152/ajpheart.01210.2004.
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Nicotine increases the permeability of the blood-brain barrier in vivo. This implies a possible role for nicotinic acetylcholine receptors in the regulation of cerebral microvascular permeability. Expression of nicotinic acetylcholine receptor subunits in cerebral microvessels was investigated with immunofluorescence microscopy. Positive immunoreactivity was found for receptor subunits α3, α5, α7, and β2, but not subunits α4, β3, or β4. Blood-brain barrier permeability was assessed via in situ brain perfusion with [14C]sucrose. Nicotine increased the rate of sucrose entry into the brain from 0.3 ± 0.1 to 1.1 ± 0.2 μl·g−1·min−1, as previously described. This nicotine-induced increase in blood-brain barrier permeability was significantly attenuated by both the blood-brain barrier-permeant nicotinic antagonist mecamylamine and the blood-brain barrier-impermeant nicotinic antagonist hexamethonium to 0.5 ± 0.2 and 0.3 ± 0.2 μl·g−1·min−1, respectively. These data suggest that nicotinic acetylcholine receptors expressed on the cerebral microvascular endothelium mediate nicotine-induced changes in blood-brain barrier permeability.
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Lavezzi, Anna. "Toxic Effect of Cigarette Smoke on Brainstem Nicotinic Receptor Expression: Primary Cause of Sudden Unexplained Perinatal Death." Toxics 6, no. 4 (October 18, 2018): 63. http://dx.doi.org/10.3390/toxics6040063.
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Among the neurotoxicants contained in tobacco smoke, if absorbed during pregnancy, nicotine significantly affects α7-nicotinic acetylcholine receptors, which play essential roles in the development of the brainstem regions receiving cholinergic projections in perinatal life. Immunohistochemical procedures for analysing formalin-fixed and paraffin-embedded brainstem samples from 68 fetuses and early newborns, with smoking and non-smoking mothers, who died of known and unknown causes, were carried out in order to determine if nicotine had activated the α7-nicotinic acetylcholine receptors. High α7-nicotinic acetylcholine receptor expression levels were only observed in the victims with smoking mothers. Frequently, these findings were associated with the hypoplasia of the brainstem structures controlling vital functions. The results of this study indicate that the exposition to nicotine in pregnancy exerts a strong direct effect on α7-nicotinic acetylcholine receptor activity especially in perinatal life and may be one of the primary risk factors leading to the sudden unexplained death of fetuses and newborns.
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White, Sean H., Christopher J. Carter, and Neil S. Magoski. "A potentially novel nicotinic receptor in Aplysia neuroendocrine cells." Journal of Neurophysiology 112, no. 2 (July 15, 2014): 446–62. http://dx.doi.org/10.1152/jn.00796.2013.
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Nicotinic receptors form a diverse group of ligand-gated ionotropic receptors with roles in both synaptic transmission and the control of excitability. In the bag cell neurons of Aplysia, acetylcholine activates an ionotropic receptor, which passes inward current to produce a long-lasting afterdischarge and hormone release, leading to reproduction. While testing the agonist profile of the cholinergic response, we observed a second current that appeared to be gated only by nicotine and not acetylcholine. The peak nicotine-evoked current was markedly smaller in magnitude than the acetylcholine-induced current, cooperative (Hill value of 2.7), had an EC50 near 500 μM, readily recovered from desensitization, showed Ca2+ permeability, and was blocked by mecamylamine, dihydro-β-erythroidine, or strychnine, but not by α-conotoxin ImI, methyllycaconitine, or hexamethonium. Aplysia transcriptome analysis followed by PCR yielded 20 full-length potential nicotinic receptor subunits. Sixteen of these were predicted to be cation selective, and real-time PCR suggested that 15 of the 16 subunits were expressed to varying degrees in the bag cell neurons. The acetylcholine-induced current, but not the nicotine current, was reduced by double-strand RNA treatment targeted to both subunits ApAChR-C and -E. Conversely, the nicotine-evoked current, but not the acetylcholine current, was lessened by targeting both subunits ApAChR-H and -P. To the best of our knowledge, this is the first report suggesting that a nicotinic receptor is not gated by acetylcholine. Separate receptors may serve as a means to differentially trigger plasticity or safeguard propagation by assuring that only acetylcholine, the endogenous agonist, initiates large enough responses to trigger reproduction.
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Wongtrakool, Cherry, Susanne Roser-Page, Hilda N. Rivera, and Jesse Roman. "Nicotine alters lung branching morphogenesis through the α7 nicotinic acetylcholine receptor." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 3 (September 2007): L611—L618. http://dx.doi.org/10.1152/ajplung.00038.2007.
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There is abundant epidemiological data linking prenatal environmental tobacco smoke with childhood asthma and wheezing, but the underlying molecular and physiological mechanisms that occur in utero to explain this link remain unelucidated. Several studies suggest that nicotine, which traverses the placenta, is a causative agent. Therefore, we studied the effects of nicotine on lung branching morphogenesis using embryonic murine lung explants. We found that the expression of α7 nicotinic acetylcholine receptors, which mediate many of the biological effects of nicotine, is highest in pseudoglandular stage lungs compared with lungs at later stages. We then studied the effects of nicotine in the explant model and found that nicotine stimulated lung branching in a dose-dependent fashion. α-Bungarotoxin, an antagonist of α7 nicotinic acetylcholine receptors, blocked the stimulatory effect of nicotine, whereas GTS-21, a specific agonist, stimulated branching, thereby mimicking the effects of nicotine. Explants deficient in α7 nicotinic acetylcholine receptors did not respond to nicotine. Nicotine also stimulated the growth of the explant. Altogether, these studies suggest that nicotine stimulates lung branching morphogenesis through α7 nicotinic acetylcholine receptors and may contribute to dysanaptic lung growth, which in turn may predispose the host to airway disease in the postnatal period.
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Kim, Jinah, Daniel S. Poole, Laura E. Waggoner, Anthony Kempf, David S. Ramirez, P. Alexandra Treschow, and William R. Schafer. "Genes Affecting the Activity of Nicotinic Receptors Involved in Caenorhabditis elegans Egg-Laying Behavior." Genetics 157, no. 4 (April 1, 2001): 1599–610. http://dx.doi.org/10.1093/genetics/157.4.1599.
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Abstract Egg-laying behavior in Caenorhabditis elegans is regulated by multiple neurotransmitters, including acetylcholine and serotonin. Agonists of nicotinic acetylcholine receptors such as nicotine and levamisole stimulate egg laying; however, the genetic and molecular basis for cholinergic neurotransmission in the egg-laying circuitry is not well understood. Here we describe the egg-laying phenotypes of eight levamisole resistance genes, which affect the activity of levamisole-sensitive nicotinic receptors in nematodes. Seven of these genes, including the nicotinic receptor subunit genes unc-29, unc-38, and lev-1, were essential for the stimulation of egg laying by levamisole, though they had only subtle effects on egg-laying behavior in the absence of drug. Thus, these genes appear to encode components of a nicotinic receptor that can promote egg laying but is not necessary for egg-laying muscle contraction. Since the levamisole-receptor mutants responded to other cholinergic drugs, other acetylcholine receptors are likely to function in parallel with the levamisole-sensitive receptors to mediate cholinergic neurotransmission in the egg-laying circuitry. In addition, since expression of functional unc-29 in muscle cells restored levamisole sensitivity under some but not all conditions, both neuronal and muscle cell UNC-29 receptors are likely to contribute to the regulation of egg-laying behavior. Mutations in one levamisole receptor gene, unc-38, also conferred both hypersensitivity and reduced peak response to serotonin; thus nicotinic receptors may play a role in regulating serotonin response pathways in the egg-laying neuromusculature.
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Entwistle, A., R. J. Zalin, A. E. Warner, and S. Bevan. "A role for acetylcholine receptors in the fusion of chick myoblasts." Journal of Cell Biology 106, no. 5 (May 1, 1988): 1703–12. http://dx.doi.org/10.1083/jcb.106.5.1703.
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The role of acetylcholine receptors in the control of chick myoblast fusion in culture has been explored. Spontaneous fusion of myoblasts was inhibited by the nicotinic acetylcholine receptor antagonists alpha-bungarotoxin, Naja naja toxin and monoclonal antibody mcAb 5.5. The muscarinic antagonists QNB and n-methyl scopolamine were without effect. Atropine had no effect below 1 microM, where it blocks muscarinic receptors; at higher concentrations, when it blocks nicotinic receptors also, atropine inhibited myoblast fusion. The inhibitions imposed by acetylcholine receptor antagonists lasted for approximately 12 h; fusion stimulated by other endogenous substances then took over. The inhibition was limited to myoblast fusion. The increases in cell number, DNA content, the level of creatine phosphokinase activity (both total and muscle-specific isozyme) and the appearance of heavy chain myosin, which accompany muscle differentiation, followed a normal time course. Pre-fusion myoblasts, fusing myoblasts, and young myotubes specifically bound labeled alpha-bungarotoxin, indicating the presence of acetylcholine receptors. The nicotinic acetylcholine receptor agonist, carbachol, induced uptake of [14C]Guanidinium through the acetylcholine receptor. Myoblasts, aligned myoblasts and young myotubes expressed the synthetic enzyme Choline acetyltransferase and stained positively with antibodies against acetylcholine. The appearance of ChAT activity in myogenic cultures was prevented by treatment with BUDR; nonmyogenic cells in the cultures expressed ChAT at a level which was too low to account for the activity in myogenic cultures. We conclude that activation of the nicotinic acetylcholine receptor is part of the mechanism controlling spontaneous myoblast fusion and that myoblasts synthesize an endogenous, fusion-inducing agent that activates the nicotinic ACh receptor.
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Singh, Sandeep, Smitha Pillai, and Srikumar Chellappan. "Nicotinic Acetylcholine Receptor Signaling in Tumor Growth and Metastasis." Journal of Oncology 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/456743.
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Cigarette smoking is highly correlated with the onset of a variety of human cancers, and continued smoking is known to abrogate the beneficial effects of cancer therapy. While tobacco smoke contains hundreds of molecules that are known carcinogens, nicotine, the main addictive component of tobacco smoke, is not carcinogenic. At the same time, nicotine has been shown to promote cell proliferation, angiogenesis, and epithelial-mesenchymal transition, leading to enhanced tumor growth and metastasis. These effects of nicotine are mediated through the nicotinic acetylcholine receptors that are expressed on a variety of neuronal and nonneuronal cells. Specific signal transduction cascades that emanate from different nAChR subunits or subunit combinations facilitate the proliferative and prosurvival functions of nicotine. Nicotinic acetylcholine receptors appear to stimulate many downstream signaling cascades induced by growth factors and mitogens. It has been suggested that antagonists of nAChR signaling might have antitumor effects and might open new avenues for combating tobacco-related cancer. This paper examines the historical data connecting nicotine tumor progression and the recent efforts to target the nicotinic acetylcholine receptors to combat cancer.
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Javadi, Parastoo, Ameneh Rezayof, Maryam Sardari, and Zahra Ghasemzadeh. "Brain nicotinic acetylcholine receptors are involved in stress-induced potentiation of nicotine reward in rats." Journal of Psychopharmacology 31, no. 7 (May 25, 2017): 945–55. http://dx.doi.org/10.1177/0269881117707745.
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The aim of the present study was to examine the possible role of nicotinic acetylcholine receptors of the dorsal hippocampus (CA1 regions), the medial prefrontal cortex or the basolateral amygdala in the effect of acute or sub-chronic stress on nicotine-induced conditioned place preference. Our results indicated that subcutaneous administration of nicotine (0.2 mg/kg) induced significant conditioned place preference. Exposure to acute or sub-chronic elevated platform stress potentiated the response of an ineffective dose of nicotine. Pre-conditioning intra-CA1 (0.5–4 µg/rat) or intra-medial prefrontal cortex (0.2–0.3 µg/rat) microinjection of mecamylamine (a non-selective nicotinic acetylcholine receptor antagonist) reversed acute stress-induced potentiation of nicotine reward as measured in the conditioned place preference paradigm. By contrast, pre-conditioning intra-basolateral amygdala microinjection of mecamylamine (4 µg/rat) potentiated the effects of acute stress on nicotine reward. Our findings also showed that intra-CA1 or intra-medial prefrontal cortex, but not intra-basolateral amygdala, microinjection of mecamylamine (4 µg/rat) prevented the effect of sub-chronic stress on nicotine reward. These findings suggest that exposure to elevated platform stress potentiates the rewarding effect of nicotine which may be associated with the involvement of nicotinic acetylcholine receptors. It seems that there is a different contribution of the basolateral amygdala, the medial prefrontal cortex or the CA1 nicotinic acetylcholine receptors in stress-induced potentiation of nicotine-induced conditioned place preference.
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Beckel, Jonathan M., Anthony Kanai, Sun-Ju Lee, William C. de Groat, and Lori A. Birder. "Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells." American Journal of Physiology-Renal Physiology 290, no. 1 (January 2006): F103—F110. http://dx.doi.org/10.1152/ajprenal.00098.2005.
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Although nicotinic acetylcholine receptors in both the central and peripheral nervous systems play a prominent role in the control of urinary bladder function, little is known regarding expression or function of nicotinic receptors in the bladder epithelium, or urothelium. Nicotinic receptors have been described in epithelial cells lining the upper gastrointestinal tract, respiratory tract, and the skin. Thus the present study examined the expression and functionality of nicotinic receptors in the urothelium, as well as the effects of stimulation of nicotinic receptors on the micturition reflex. mRNA for the α3, α5, α7, β3, and β4 nicotinic subunits was identified in rat urothelial cells using RT-PCR. Western blotting also confirmed urothelial expression of the α3- and α7-subunits. Application of nicotine (50 nM) to cultured rat urothelial cells elicited an increase in intracellular Ca2+ concentration, indicating that at least some of the subunits form functional channels. These effects were blocked by the application of the nicotinic antagonist hexamethonium. During in vivo bladder cystometrograms in urethane-anesthetized rats, intravesical administration of nicotine, choline, or the antagonists methyllycaconitine citrate and hexamethonium elicited changes in voiding parameters. Intravesical nicotine (50 nM, 1 μM) increased the intercontraction interval. Intravesical choline (1–100 μM) also affected bladder reflexes similarly, suggesting that α7 nicotinic receptors mediate this effect. Intravesical administration of hexamethonium (1–100 μM) potentiated the nicotine-induced changes in bladder reflexes. Methyllycaconitine citrate, a specific α7-receptor antagonist, prevented nicotine-, choline-, and hexamethonium-induced bladder inhibition. These results are the first indication that stimulation of nonneuronal nicotinic receptors in the bladder can affect micturition.
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MANEU, VICTORIA, GUILLERMO GERONA, LAURA FERNÁNDEZ, NICOLÁS CUENCA, and PEDRO LAX. "Evidence of alpha 7 nicotinic acetylcholine receptor expression in retinal pigment epithelial cells." Visual Neuroscience 27, no. 5-6 (October 8, 2010): 139–47. http://dx.doi.org/10.1017/s0952523810000246.
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AbstractSome evidence suggests that retinal pigment epithelium (RPE) can express nicotinic acetylcholine receptors (nAChRs) as described for other epithelial cells, where nAChRs have been involved in processes such as cell development, cell death, cell migration, and angiogenesis. This study is designed to determine the expression and activity of α7 nAChRs in RPE cells. Reverse transcriptase (RT)-PCR was performed to test the expression of nicotinic α7 subunit in bovine RPE cells. Protein expression was determined by Western blot and by immunocytochemistry. Expression of nicotinic α7 subunits was also analyzed in cryostat sections of albino rat retina. Changes in protein expression were tested under hypoxic conditions. Functional nAChRs were studied by examining the Ca2+transients elicited by nicotine and acetylcholine stimulation in fura-2–loaded cells. Expression of endogenous modulators of nAChRs was analyzed by RT-PCR and Western blot in retina and RPE. Cultured bovine RPE cells expressed nicotinic receptors containing α7 subunit. RT-PCR amplified the expected specific α7 fragment. Western blotting showed expression at the protein level, with a specific band being found at 57 kDa in both cultured and freshly isolated RPE cells. Expression of nAChRs was confirmed for cultured cells by immunofluorescence. Immunohistochemistry confirmed α7 receptor expression in rat RPE retina. α7 receptor expression was down-regulated by long-term hypoxia. A small subpopulation of RPE cultured cells showed functional nAChRs, as evidenced by the selective response elicited by nicotine and acetylcholine stimulation. Expression of the endogenous nicotinic receptors’ modulator lynx1 was confirmed in bovine retina and RPE, and expression of lynx1 and other endogenous nicotinic receptor modulators (SLURP1 and RGD1308195) were also confirmed in rat retina. These results suggest that nAChRs could have a significant role in RPE, which may not be related to the traditional role in nerve transmission but could more likely be related to the nonneuronal cholinergic system in the eye.
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Jones, Candace. "α7 Nicotinic Acetylcholine Receptor." Journal of Clinical Psychopharmacology 38, no. 3 (June 2018): 247–49. http://dx.doi.org/10.1097/jcp.0000000000000859.
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Steinlein, Ortrud K., Sunao Kaneko, and Shinichi Hirose. "Nicotinic acetylcholine receptor mutations." Epilepsia 51 (December 2010): 65. http://dx.doi.org/10.1111/j.1528-1167.2010.02851.x.
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Dani, John A. "Nicotinic Receptor Activity Alters Synaptic Plasticity." Scientific World JOURNAL 1 (2001): 393–95. http://dx.doi.org/10.1100/tsw.2001.74.
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Studies using specific agonists, antagonists, and lesions have shown that nicotinic cholinergic systems participate in attention, learning, and memory[1,2]. The nicotinic manipulations usually have the greatest influence on difficult tasks or on cognitively impaired subjects[2]. For example, Alzheimer's disease is characterized by a loss of cholinergic projections and nicotinic acetylcholine receptors (nAChRs) in the cortex and hippocampus[3]. Nicotine skin patches can improve learning rates and attention in Alzheimer's patients[4].
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Hedrick, Tristan, and Jack Waters. "Acetylcholine excites neocortical pyramidal neurons via nicotinic receptors." Journal of Neurophysiology 113, no. 7 (April 2015): 2195–209. http://dx.doi.org/10.1152/jn.00716.2014.
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The neuromodulator acetylcholine (ACh) shapes neocortical function during sensory perception, motor control, arousal, attention, learning, and memory. Here we investigate the mechanisms by which ACh affects neocortical pyramidal neurons in adult mice. Stimulation of cholinergic axons activated muscarinic and nicotinic ACh receptors on pyramidal neurons in all cortical layers and in multiple cortical areas. Nicotinic receptor activation evoked short-latency, depolarizing postsynaptic potentials (PSPs) in many pyramidal neurons. Nicotinic receptor-mediated PSPs promoted spiking of pyramidal neurons. The duration of the increase in spiking was membrane potential dependent, with nicotinic receptor activation triggering persistent spiking lasting many seconds in neurons close to threshold. Persistent spiking was blocked by intracellular BAPTA, indicating that nicotinic ACh receptor activation evoked persistent spiking via a long-lasting calcium-activated depolarizing current. We compared nicotinic PSPs in primary motor cortex (M1), prefrontal cortex (PFC), and visual cortex. The laminar pattern of nicotinic excitation was not uniform but was broadly similar across areas, with stronger modulation in deep than superficial layers. Superimposed on this broad pattern were local differences, with nicotinic PSPs being particularly large and common in layer 5 of M1 but not layer 5 of PFC or primary visual cortex (V1). Hence, in addition to modulating the excitability of pyramidal neurons in all layers via muscarinic receptors, synaptically released ACh preferentially increases the activity of deep-layer neocortical pyramidal neurons via nicotinic receptors, thereby adding laminar selectivity to the widespread enhancement of excitability mediated by muscarinic ACh receptors.
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Li, Xinhui, and James C. Eisenach. "Nicotinic Acetylcholine Receptor Regulation of Spinal Norepinephrine Release." Anesthesiology 96, no. 6 (June 1, 2002): 1450–56. http://dx.doi.org/10.1097/00000542-200206000-00026.
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Background Neuronal nicotinic acetylcholine receptor (nAChR) agonists produce antinociception in animals. nAChRs exist almost exclusively on presynaptic terminals in the central nervous system and stimulate neurotransmitter release. This study tested whether nAChR agonists stimulate spinal release of the neurotransmitter norepinephrine either by direct actions on noradrenergic terminals or indirectly by stimulating release of other neurotransmitters to induce norepinephrine release. Methods Adult male rats were anesthetized and microdialysis probes inserted in the L2-L4 dermatomes of the spinal cord. Probes were perfused with artificial cerebrospinal fluid containing nicotine, the specific alpha(4)beta(2*) nAChR agonist metanicotine, or nicotine plus nAChR antagonists and norepinephrine measured in the microdialysates. The effects of specific glutamate receptor antagonists and nitric oxide synthase inhibitors were also examined. To determine direct effects on noradrenergic terminals, synaptosomes were prepared from spinal cord and incubated with nAChR agonists and antagonists. Results Both nicotine and metanicotine induced norepinephrine release in spinal microdialsyates, an effect reduced by nicotinic antagonists but not glutamate antagonists or nitric oxide synthase inhibitors. Both of the nicotinic agonists stimulated norepinephrine release in synaptosomes, and the effect of metanicotine was blocked at lower concentrations of alpha(4)beta(2*)- than alpha(7*)-preferring nAChR antagonists. Conclusion These results suggest that one mechanism by which nAChR agonists act for analgesia is to stimulate spinal norepinephrine release. They do so by actions on alpha(4)beta(2*) nAChRs, and perhaps other subtypes, most likely located on noradrenergic terminals, rather than by indirectly stimulating norepinephrine release through glutamate release or nitric oxide synthesis.
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Sharma, Geeta, and Sukumar Vijayaraghavan. "Nicotinic Receptors: Role in Addiction and Other Disorders of the Brain." Substance Abuse: Research and Treatment 1 (January 2008): 117822180800100. http://dx.doi.org/10.1177/117822180800100005.
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Nicotine, the addictive component of cigarette smoke has profound effects on the brain. Activation of its receptors by nicotine has complex consequences for network activity throughout the brain, potentially contributing to the addictive property of the drug. Nicotinic receptors have been implicated in psychiatric illnesses like schizophrenia and are also neuroprotective, potentially beneficial for neurodegenerative diseases. These effects of nicotine serve to emphasize the multifarious roles the drug, acting through multiple nicotinic acetylcholine receptor subtypes. The findings also remind us of the complexity of signaling mechanisms and stress the risks of unintended consequences of drugs designed to combat nicotine addiction.
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Raines, Douglas E., Robert J. Claycomb, Michaela Scheller, and Stuart A. Forman. "Nonhalogenated Alkane Anesthetics Fail to Potentiate Agonist Actions on Two Ligand-gated Ion Channels." Anesthesiology 95, no. 2 (August 1, 2001): 470–77. http://dx.doi.org/10.1097/00000542-200108000-00032.
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Background Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and y-aminobutyric acid type A (GABA(A)) receptor. Methods Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA(A) receptors (alpha1beta2gamma2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A) receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. Results Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. Conclusions Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.
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Zhang, Chuan-Li, Yakov Verbny, Sameh A. Malek, Peter K. Stys, and Shing Yan Chiu. "Nicotinic Acetylcholine Receptors in Mouse and Rat Optic Nerves." Journal of Neurophysiology 91, no. 2 (February 2004): 1025–35. http://dx.doi.org/10.1152/jn.00769.2003.
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Receptor-mediated calcium signaling in axons of mouse and rat optic nerves was examined by selectively staining the axonal population with a calcium indicator. Nicotine (1-50 μM) induced an axonal calcium elevation that was eliminated when calcium was removed from the bath, suggesting that nicotine induces calcium influx into axons. The nicotine response was blocked by d-tubocurarine and mecamylamine but not α-bungarotoxin, indicating the presence of calcium permeable, non-α7 nicotinic acetylcholine receptor (nAChR) subtype. Agonist efficacy order for eliciting the axonal nAChR calcium response was cytisine ∼ nicotine >> acetylcholine. The nicotine-mediated calcium response was attenuated during the process of normal myelination, decreasing by approximately 10-fold from P1 (premyelinated) to P30 (myelinated). Nicotine also caused a rapid reduction in the compound action potential in neonatal optic nerves, consistent with a shunting of the membrane after opening of the nonspecific cationic nicotinic channels. Voltagegated calcium channels contributed little to the axonal calcium elevation during nAChR activation. During repetitive stimulations, the compound action potential in neonatal mouse optic nerves underwent a gradual reduction in amplitude that could be partially prevented by d-tubocurarine, suggesting an activity-dependent release of acetylcholine that activates axonal AChRs. We conclude that mammalian optic nerve axons express nAChRs and suggest that these receptors are activated in an activity-dependent fashion during optic nerve development to modulate axon excitability and biology.
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Liu, Tao, Tsugumi Fujita, and Eiichi Kumamoto. "Acetylcholine and norepinephrine mediate GABAergic but not glycinergic transmission enhancement by melittin in adult rat substantia gelatinosa neurons." Journal of Neurophysiology 106, no. 1 (July 2011): 233–46. http://dx.doi.org/10.1152/jn.00838.2010.
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GABAergic and glycinergic inhibitory synaptic transmissions in substantia gelatinosa (SG; lamina II of Rexed) neurons of the spinal dorsal horn play an important role in regulating nociceptive transmission from the periphery. It has not yet been well known whether each of the inhibitory transmissions plays a distinct role in the regulation. We report an involvement of neurotransmitters in GABAergic but not glycinergic transmission enhancement produced by the PLA2 activator melittin, where the whole-cell patch-clamp technique is applied to the SG neurons of adult rat spinal cord slices. Glycinergic but not GABAergic spontaneous inhibitory postsynaptic current (sIPSC) was increased in frequency and amplitude by melittin in the presence of nicotinic, muscarinic acetylcholine, and α1-adrenergic receptor antagonists (mecamylamine, atropine, and WB-4101, respectively). GABAergic transmission enhancement produced by melittin was unaffected by the 5-hydroxytryptamine 3 receptor and P2X receptor antagonists (ICS-205,930 and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid, respectively). Nicotinic and muscarinic acetylcholine receptor agonists [(−)-nicotine and carbamoylcholine, respectively] and norepinephrine, as well as melittin, increased GABAergic sIPSC frequency and amplitude. A repeated application of (−)-nicotine, carbamoylcholine, and norepinephrine, but not melittin, at an interval of 30 min produced a similar transmission enhancement. These results indicate that melittin produces the release of acetylcholine and norepinephrine, which activate (nicotinic and muscarinic) acetylcholine and α1-adrenergic receptors, respectively, resulting in GABAergic but not glycinergic transmission enhancement in SG neurons. The desensitization of a system leading to the acetylcholine and norepinephrine release is slow in recovery. This distinction in modulation between GABAergic and glycinergic transmissions may play a role in regulating nociceptive transmission.
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Ros, Esteve, Jordi Aleu, Inmaculada Gomez De Aranda, Carles Cantí, Yuan-Ping Pang, Jordi Marsal, and Carles Solsona. "Effects of Bis(7)-Tacrine on Spontaneous Synaptic Activity and on the Nicotinic ACh Receptor of Torpedo Electric Organ." Journal of Neurophysiology 86, no. 1 (July 1, 2001): 183–89. http://dx.doi.org/10.1152/jn.2001.86.1.183.
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Bis(7)-tacrine is a potent acetylcholinesterase inhibitor in which two tacrine molecules are linked by a heptylene chain. We tested the effects of bis(7)-tacrine on the spontaneous synaptic activity. Miniature endplate potentials (MEPPs) were recorded extracellularly on slices of electric organ of Torpedo marmorata. Bis(7)-tacrine, at a concentration of 100 nM, increased the magnitudes that describe MEPPs: amplitude, area, rise time, rate of rise, and half-width. We also tested the effect of bis(7)-tacrine on nicotinic acetylcholine receptors by analyzing the currents elicited by acetylcholine (100 μM) in Torpedo electric organ membranes transplanted in Xenopus laevis oocytes. Bis(7)-tacrine inhibited the acetylcholine-induced currents in a reversible manner (IC50 = 162 nM). The inhibition of nicotinic acetylcholine receptors was not voltage dependent, and bis(7)-tacrine increased the desensitization of nicotinic acetylcholine receptors. The Hill coefficient for bis(7)-tacrine was −0.72 ± 0.02, indicating that bis(7)-tacrine binds to the nicotinic acetylcholine receptor in a molecular ratio of 1:1, but does not affect the binding of α-bungarotoxin with the nicotinic acetylcholine receptor. In conclusion, bis(7)-tacrine greatly increases the spontaneous quantal release from peripheral cholinergic terminals at a much lower concentration than tacrine. Bis(7)-tacrine also blocks acetylcholine-induced currents of Torpedo electric organ, although the mechanism is different from that of tacrine: bis(7)-tacrine enhances desensitization, whereas tacrine reduces it.
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Koyama, S., S. I. Rennard, and R. A. Robbins. "Acetylcholine stimulates bronchial epithelial cells to release neutrophil and monocyte chemotactic activity." American Journal of Physiology-Lung Cellular and Molecular Physiology 262, no. 4 (April 1, 1992): L466—L471. http://dx.doi.org/10.1152/ajplung.1992.262.4.l466.
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Bronchial asthma is accompanied by inflammatory cell infiltration in the airway. Increased bronchial reactivity to cholinergic stimulation is well recognized in patients with bronchial asthma. Thus, we postulated that acetylcholine (ACh) stimulates bronchial epithelial cells (BEC) to release neutrophil and monocyte chemotactic activity (NCA and MCA). To test this hypothesis, bovine BEC monolayers were tested for NCA and MCA by a blind-well chemotactic chamber technique. BEC released NCA and MCA in response to ACh in a dose-dependent and time-dependent manner. Molecular sieve column chromatography revealed that ACh induced a single low-molecular-weight peak (near 400) for NCA and two low-molecular-weight peaks (near 12,000 and 400) for MCA. The release of NCA and MCA was inhibited by the lipoxygenase inhibitors, nordihydroguaiaretic acid and diethylcarbamazine. Cigarette smoke is a well-recognized stimulus for airway inflammation. To determine whether smoke might activate BEC to release NCA by stimulating nicotinic ACh receptors, we further characterized the ACh receptors, using nicotine and nicotinic and muscarinic receptor antagonists. Nicotine, the nicotinic receptor antagonist d-tubocurarine, and the M2 receptor antagonist gallamine did not modulate the release of NCA in response to ACh. In contrast, atropine and the M1 receptor antagonist, pirenzepine, inhibited the release of NCA. These data demonstrate that ACh stimulates BEC to release lipoxygenase-derived NCA and MCA through the muscarinic receptor.
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Skok, Vladimir I. "Molecular mechanisms of open-channel blockade in nicotinic acetylcholine receptors of autonomic ganglia neurons." Canadian Journal of Physiology and Pharmacology 70, S1 (May 15, 1992): S78—S85. http://dx.doi.org/10.1139/y92-247.
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The results of recent attempts to estimate the dimensions of ionic channels in nicotinic acetylcholine receptors of sympathetic and enteric ganglia neurons are reviewed. The channel dimensions, obtained from comparison of the sizes of the open-channel blocking molecules with their blocking activities, are 6.1 × 8.3 Å (1 Å = 0.1 nm) in both sympathetic and enteric ganglia. None of the competitive ganglionic blockers fit within this channel size. In addition, a chemical structure that binds the open-channel blockers in ganglionic nicotinic acetylcholine receptors is suggested to be formed by serine and threonine residues, as found by comparing the differences between the structures of the neuronal and muscle nicotinic acetylcholine receptors with the differences in their pharmacology.Key words: nicotinic acetylcholine receptor, autonomic ganglia, open-channel blocking mechanisms.
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Lee, Chia-Hwa, Chih-Hsiung Wu, and Yuan-Soon Ho. "From Smoking to Cancers: Novel Targets to Neuronal Nicotinic Acetylcholine Receptors." Journal of Oncology 2011 (2011): 1–10. http://dx.doi.org/10.1155/2011/693424.
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Cigarette smoking bears a strong etiological association with many neovascularization-related diseases, including cancer, cardiovascular disease, and age-related macular degeneration. Cigarette smoke is a complex mixture of many compounds, including nicotine, which is the major active and addictive component of tobacco. Nicotine and its specific metabolized carcinogens directly bind to nicotinic acetylcholine receptors (nAChRs) on cell membranes and trigger the nAChR signal cascade. The nAChRs were originally thought to be ligand-gated ion channels that modulate physiological processes ranging from neurotransmission to cancer signaling. For several decades, the nAChRs served as a prototypic molecule for neurotransmitter receptors; however, they are now important therapeutic targets for various diseases, including Alzheimer's and Parkinson's diseases, schizophrenia, and even cancer. This paper describes recent advances in our understanding of the assembly, activity, and biological functions of nicotinic receptors, as well as developments in the therapeutic application of nicotinic receptor ligands.
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COLQUHOUN, L., L. HOLDEN-DYE, and R. J. WALKER. "The Pharmacology of Cholinoceptors on the Somatic Muscle Cells of the Parasitic Nematode Ascaris Suum." Journal of Experimental Biology 158, no. 1 (July 1, 1991): 509–30. http://dx.doi.org/10.1242/jeb.158.1.509.
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1. Acetylcholine (ACh) elicited depolarization and an increase in input conductance of the somatic muscle cells of the parasitic nematode Ascaris suum. 2. The relative potency of nicotinic and muscarinic agents was studied in this preparation. The order of potency of these compounds was metahydroxyphenylpropyltrimethylammonium (HPPT)> 1,1 dimethyl-4-phenylpiperazinium>(DMPP)> ACh> carbachol> nicotine> tetramethylammonium (TMA+)> muscarone> furtrethonium> arecoline. Decamethonium was also a weak agonist. McN-A-343 elicited a very weak depolarization at concentrations above 1 mmoll−1. Bethanechol and methacholine were without effect up to 1 mmoll−1. Pilocarpine and muscarine elicited a slight hyperpolarization of up to 3 mV with a threshold for the response of around 500 μmoll−1. Oxotremorine (1 mmoll−1) was without effect. 3. The nitromethylene insecticide 2(nitromethylene)tetrahydro 1,3-thiazine (NMTHT), an agonist at insect nicotinic receptors, was without effect on Ascaris muscle cells up to 1 mmoll−1. 4. Mecamylamine and benzoquinonium were the most potent antagonists of the acetylcholine response. The order of potency of the other antagonists was tetraphenylphosphonium (TPP) > quinacrine > pancuronium, curare> trimethaphan> atropine chlorisondamine, decamethonium > hexamethonium > dihydro-/3-ery throidine. 5. The agonist profile of the Ascaris muscle cell ACh receptor clearly indicates that it is nicotinic. The potency of ganglionic and neuromuscular nicotinic receptor antagonists in Ascaris does not enable a further subclassification of this nicotinic receptor. The Ascaris nicotinic receptor seems to possess some of the pharmacological properties of each type of vertebrate nicotinic receptor. The pharmacology of the Ascaris nicotinic receptor is discussed in relation to that of nicotinic receptors in other invertebrate preparations and in vertebrate preparations. Note: To whom reprint requests should be addressed.
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Lang, P. M., R. Burgstahler, W. Sippel, D. Irnich, B. Schlotter-Weigel, and P. Grafe. "Characterization of Neuronal Nicotinic Acetylcholine Receptors in the Membrane of Unmyelinated Human C-Fiber Axons by In Vitro Studies." Journal of Neurophysiology 90, no. 5 (November 2003): 3295–303. http://dx.doi.org/10.1152/jn.00512.2003.
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Application of acetylcholine to peripheral nerve terminals in the skin is a widely used test in studies of human small-fiber functions. However, a detailed pharmacological profile and the subunit composition of nicotinic acetylcholine receptors in human C-fiber axons are not known. In the present study, we recorded acetylcholine-induced changes of the excitability and of the intracellular Ca2+ concentration in C-fiber axons of isolated human nerve segments. In addition, using immunohistochemistry, an antibody of a subtype of nicotinic acetylcholine receptor was tested. Acetylcholine and agonists reduced the current necessary for the generation of action potentials in C fibers by ≤30%. This increase in axonal excitability was accompanied by a rise in the free intracellular Ca2+ concentration. The following rank order of potency for agonists was found: epibatidine >> 5-Iodo-A-85380 > 1,1-dimethyl-4-phenylpiperazinium iodide > nicotine > cytisine > acetylcholine; choline had no effect. The epibatidine-induced increase in axonal excitability was blocked by mecamylamine and, less efficiently, by methyllycacontine and dihydro-β-erythroidine. Many C-fiber axons were labeled by an antibody that recognizes the α5 subunit of nicotinic acetylcholine receptors. In summary, electrophysiological and immunohistochemical data indicate the functional expression of nicotinic acetylcholine receptors composed of α3, α5, and β4 but not of α4/β2 or of α7 subunits in the axonal membrane of unmyelinated human C fibers. In addition, the observations suggest that the axonal membrane of C fibers in isolated segments of human sural nerve can be used as a model for presumed cholinergic chemosensitivity of axonal terminals.
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Strang, Christianne E., Ye Long, Konstantin E. Gavrikov, Franklin R. Amthor, and Kent T. Keyser. "Nicotinic and muscarinic acetylcholine receptors shape ganglion cell response properties." Journal of Neurophysiology 113, no. 1 (January 1, 2015): 203–17. http://dx.doi.org/10.1152/jn.00405.2014.
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The purpose of this study was to evaluate the expression patterns of nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively) in relation to one another and to understand their effects on rabbit retinal ganglion cell response properties. Double-label immunohistochemistry revealed labeled inner-retinal cell bodies and complex patterns of nAChR and mAChR expression in the inner plexiform layer. Specifically, the expression patterns of m1, m4, and m5 muscarinic receptors overlapped with those of non-α7 and α7 nicotinic receptors in presumptive amacrine and ganglion cells. There was no apparent overlap in the expression patterns of m2 muscarinic receptors with α7 nicotinic receptors or of m3 with non-α7 nicotinic receptors. Patch-clamp recordings demonstrated cell type-specific effects of nicotinic and muscarinic receptor blockade. Muscarinic receptor blockade enhanced the center responses of brisk-sustained/G4 On and G4 Off ganglion cells, whereas nicotinic receptor blockade suppressed the center responses of G4 On-cells near the visual streak but enhanced the center responses of nonstreak G4 On-cells. Blockade of muscarinic or nicotinic receptors suppressed the center responses of brisk-sustained Off-cells and the center light responses of subsets of brisk-transient/G11 On- and Off-cells. Only nicotinic blockade affected the center responses of G10 On-cells and G5 Off-cells. These data indicate that physiologically and morphologically identified ganglion cell types have specific patterns of AChR expression. The cholinergic receptor signatures of these cells may have implications for understanding visual defects in disease states that result from decreased ACh availability.
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Deneris, E. S., J. Boulter, J. Connolly, E. Wada, K. Wada, D. Goldman, L. W. Swanson, J. Patrick, and S. Heinemann. "Genes encoding neuronal nicotinic acetylcholine receptors." Clinical Chemistry 35, no. 5 (May 1, 1989): 731–37. http://dx.doi.org/10.1093/clinchem/35.5.731.
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Abstract Four genes (alpha 2, alpha 3, alpha 4, and beta 2), which encode proteins homologous to the Torpedo electric organ and vertebrate muscle nicotinic acetylcholine receptors, have been identified by cloning rat brain cDNAs. Injection of transcripts derived from these cDNAs into Xenopus laevis oocytes results in the formation of three nicotinic acetylcholine receptors. Two of these receptors, alpha 3/beta 2 and alpha 4/beta 2, have the characteristics of ganglionic nicotinic receptors. The third (alpha 2/beta 2) exhibits a previously undescribed pharmacology and thus represents a novel subtype that may be expressed in the brain. The wide distribution of alpha 2, alpha 3, alpha 4, and beta 2 transcripts in the brain indicates that neuronal nicotinic acetylcholine receptors are a major neurotransmitter receptor system.
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Utkin, Yuri N. "Aging Affects Nicotinic Acetylcholine Receptors in Brain." Central Nervous System Agents in Medicinal Chemistry 19, no. 2 (August 6, 2019): 119–24. http://dx.doi.org/10.2174/1871524919666190320102834.
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Background: Aging is a common and inevitable stage in the life cycle of higher organisms. Different organs, including the central nervous system, are affected by aging in different ways. Many processes are involved in aging, and neurodegeneration is one of the aging processes in which the central nervous system is engaged. Brain degeneration during normal aging underlies cognitive disorders experienced by older people. Not all molecular mechanisms associated with age-related neurodegeneration are fully understood; however, there is a whole range of data on the participation of nicotinic acetylcholine receptors in the processes of aging and neurodegeneration. Two main subtypes of nicotinic acetylcholine receptor α7 and α4β2 present in the central nervous system are affected by these processes. The loss of these receptor subtypes during normal aging is one of the reasons for the cognitive impairments. The decrease in nicotinic acetylcholine receptors is also very important for the pathogenesis of age-related neurodegenerative diseases. Thus, the drugs enhancing receptor functions may be considered promising for the treatment of cognitive dysfunction in the aged people. Conclusion: To achieve healthy longevity, the molecular processes that occur during aging should be established. In this regard, the participation and role of nicotinic acetylcholine receptors in the brain aging and degeneration are considered in this review.
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McDonald, Ian A., Jean-Michel Vernier, Nicholas Cosford, and Janis Corey-Naeve. "Neuronal Nicotinic Acetylcholine Receptor Agonists." Current Pharmaceutical Design 2, no. 4 (August 1996): 357–66. http://dx.doi.org/10.2174/1381612802666220925201454.
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In contrast to the considerable effort over many years to design agonists of the muscanmc acetylcholine receptor, until recently little attention has been directed towards agonists of the nicotinic family of acetylcholine receptors (NAChRs). Nevertheless, the structure and function of NAChRs has been a topic of intense research for several decades. Currently available NAChR agonists were discovered either as natural products or have been the result of limited structure-activity relationship studies based on natural products. These agonists were initially identified in classical ligand binding assays and characterized by various in vitro and in vivo models using rodents or rodent tissue preparations. Recent advances in the molecular biology of NAChRs have allowed the generation of stable cell lines expressing recombinant human NAChRs. The incorporation of the .e cell lines into high throughput functional screening assays has stimulated the search for novel, subtype selective NAChR agonists which should have therapeutic utility for the treatment of a number ofCNS disorders, such as Alzheimer's disease, Parkinson's disease, attention deficit disorder and schizophrenia. Some of these agents, for example SIB-1508Y, ABT-418 and DMXB (GTS 21), are presently helping to establish the clinical utility of nicotinic agonists in these diseases. This review focuses on the molecular biology of NAChRs, the development of cell-based functional assays, and the use of these assays to critically support structure-activity relationship studies of two series of compounds from our own laboratories.
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Toma, Lucio, Daniela Barlocco, and Arianna Gelain. "Neuronal nicotinic acetylcholine receptor agonists." Expert Opinion on Therapeutic Patents 14, no. 7 (July 2004): 1029–40. http://dx.doi.org/10.1517/13543776.14.7.1029.
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Bahk, W. M., Y. S. Woo, H. J. Seo, B. H. Yoon, D. I. Jon, Y. J. Kwon, K. H. Lee, K. J. Min, S. Y. Lee, and H. R. Wang. "Nicotinic acetylcholine receptor antagonists for treatment-resistant depression: A meta-analysis." European Psychiatry 33, S1 (March 2016): s226. http://dx.doi.org/10.1016/j.eurpsy.2016.01.559.
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ObjectiveEmerging preclinical and clinical evidence suggests a potential role of nicotinic acetylcholine receptors in the pathophysiology of depression. Several clinical trials have investigated the efficacy of nicotinic acetylcholine receptor antagonists in treatment-resistant depression. We performed this meta-analysis to investigate whether nicotinic acetylcholine receptor antagonists significantly improve symptoms in patients with major depressive disorder who have an inadequate response to standard antidepressant therapy.MethodsA comprehensive literature search identified 6 randomized controlled trials. These 6 trials, which included 2067 participants, were pooled for this meta-analysis using a random-effects model.ResultsNicotinic acetylcholine receptor antagonists failed to show superior efficacy compared to placebo in terms of the mean change in the Montgomery-Asberg Depression Rating Scale (MADRS) score [mean difference = –0.12 (95% CI = –0.96 to 0.71); response rate (risk ratio [RR] = 0.92 (95% CI = 0.83 to 1.02)); and remission rate [RR] = 1.01 (95% CI= 0.83 to 1.23)].ConclusionThis meta-analysis failed to confirm preliminary positive evidence for the efficacy of nicotinic acetylcholine receptor antagonists in treatment-resistant depression. Further studies investigating the efficacy of various alternative treatment strategies for treatment-resistant depression will help clinicians to better understand and choose better treatment options for these populations.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Trailovic, Sasa, Sasa Ivanovic, Jelena Trailovic-Nedeljkovic, and Alan Robertson. "Pharmacological receptors of nematoda as target points for action of antiparasitic drugs." Veterinarski glasnik 64, no. 3-4 (2010): 253–64. http://dx.doi.org/10.2298/vetgl1004253t.
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Cholinergic receptors of parasitic nematodes are one of the most important possible sites of action of antiparasitic drugs. This paper presents some of our own results of electrophysiological and pharamcological examinations of nicotinic and muscarinic receptors of nematodes, as well as data from literature on a new class of anthelmintics that act precisely on cholinergic receptors. The nicotinic acetylcholine receptor (nAChR) is located on somatic muscle cells of nematodes and it is responsible for the coordination of parasite movement. Cholinomimetic anthelmintics act on this receptor, as well as acetylcholine, an endogenic neurotransmitter, but they are not sensitive to enzyme acetylcholineesterase which dissolves acetylcholine. As opposed to the nicotinic receptor of vertebra, whose structure has been examined thoroughly, the stoichiometry of the nicotinic receptor of nematodes is not completely known. However, on the grounds of knowledge acquired so far, a model has been constructed recently of the potential composition of a type of nematodes nicotinic receptor, as the site of action of anthelmintics. Based on earlier investigations, it is supposed that a conventional muscarinic receptor exists in nematodes as well, so that it can also be a new pharamocological target for the development of antinematode drugs. The latest class of synthesized anthelmintics, named aminoacetonitriles (AAD), act via the nicotinic receptor. Monepantel is the first drug from the AAD group as a most significant candidate for registration in veterinary medicine. Even though several groups of cholinomimetic anthelmintics (imiodazothiazoles, tetrahydropyrimidines, organophosphat anthelmintics) have been in use in veterinary practice for many years now, it is evident that cholinergic receptors of nematodes still present an attractive place in the examinations and development of new antinematode drugs. .
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Christophe, Elodie, Aline Roebuck, Jochen F. Staiger, Daniel J. Lavery, Serge Charpak, and Etienne Audinat. "Two Types of Nicotinic Receptors Mediate an Excitation of Neocortical Layer I Interneurons." Journal of Neurophysiology 88, no. 3 (September 1, 2002): 1318–27. http://dx.doi.org/10.1152/jn.2002.88.3.1318.
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Nicotinic acetylcholine receptors are widely expressed in the neocortex but their functional roles remain largely unknown. Here we investigated the effect of nicotinic receptor activation on interneurons of layer I, which contains a high density of cholinergic fiber terminals. Ninety-seven of 101 neurons recorded in whole cell configuration in rat acute slices were excited by local pressure application of nicotinic agonists, acetylcholine (500 μM), 1,1-dimethyl-4-phenyl-piperazinium (500 μM) or choline (10 mM). Biocytin labeling confirmed that our sample included different morphological types of layer I interneurons. The responses to nicotinic agonists persisted in presence of glutamate and muscarinic receptor antagonists and on further addition of Cd2+ or tetrodotoxin, indicating that they were mediated by direct activation of postsynaptic nicotinic receptors. The kinetics of the currents and their sensitivity to nicotinic receptor antagonists, methyllycaconitine (1–10 nM) or dihydro-β-erythroidine (500 nM), suggested that early and late components of the responses were mediated by α7 and non-α7 types of receptors. Both components had inwardly rectifying I-V curves, which differed when intracellular spermine was omitted. Single-cell RT-PCR experiments identified α4, α7, and β2 as the predominantly expressed mRNAs, suggesting that the receptors consisted of α7 homomers and α4β2 heteromers. Finally, selective excitation of layer I interneurons through activation of their nicotinic receptors resulted in a tetrodotoxin-sensitive increase of inhibitory synaptic currents recorded in nonpyramidal cells but not in pyramidal cells of layer II/III. These results suggest that acetylcholine released in layer I may induce a disinhibition of the cortical network through activation of nicotinic receptors expressed by layer I interneurons.
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KERR, K. P., J. E. STEVENSON, and F. MITCHELSON. "Simultaneous Comparison of Nicotinic Receptor Antagonists on Three Nicotinic Acetylcholine Receptors." Journal of Pharmacy and Pharmacology 47, no. 12A (December 1995): 1002–6. http://dx.doi.org/10.1111/j.2042-7158.1995.tb03286.x.
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Ho, Kenny K., and Pamela Flood. "Single Amino Acid Residue in the Extracellular Portion of Transmembrane Segment 2 in the Nicotinic α7 Acetylcholine Receptor Modulates Sensitivity to Ketamine." Anesthesiology 100, no. 3 (March 1, 2004): 657–62. http://dx.doi.org/10.1097/00000542-200403000-00028.
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Background Ketamine inhibits the activation of both heteromeric and homomeric nicotinic acetylcholine receptors. The site of molecular interaction is unknown. Methods The inhibition of alpha7 nicotinic acetylcholine receptors by ketamine was compared to that of 5-hydroxytryptamine-3A (5HT3A) receptors that are resistant to ketamine inhibition in Xenopus laevis oocytes. To determine whether the region of transmembrane segments 2 and 3 is relevant for ketamine inhibition of nicotinic receptors, the authors identified single amino acid residues that differ in the sequence alignment of the two proteins. They created 22 mutant alpha7 nicotinic receptors that contain the single homologous amino acid residue in the 5HT3A sequence. Results Of the 22 mutant alpha7 nicotinic receptors tested, only one (alpha7 A258S) was significantly resistant to 20 microM ketamine. The ketamine concentration response relationship for the alpha7 A258S mutant was shifted to the right with the IC50 for ketamine increased from 17 +/- 2 for wild type to 30 +/- 3 microM in the mutant (P < 0.001). Agonist activation was unchanged by the mutation. The homologous amino acid residue in the 5HT3A receptor was mutated to the alanine that occurs in the wild-type nicotinic receptor. This mutation made the previously insensitive 5HT3A receptor sensitive to ketamine (P < 0.001). Conclusions Conservative mutation of a single amino acid in the extracellular transmembrane segment 2 domain induces resistance to ketamine inhibition in the alpha7 nicotinic receptor and sensitivity to inhibition in the 5HT3A receptor. This region may represent a ketamine binding site in the alpha7 nicotinic receptor, or it may be an important transduction site for ketamine action.
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Genzen, Jonathan R., William Van Cleve, and Daniel S. McGehee. "Dorsal Root Ganglion Neurons Express Multiple Nicotinic Acetylcholine Receptor Subtypes." Journal of Neurophysiology 86, no. 4 (October 1, 2001): 1773–82. http://dx.doi.org/10.1152/jn.2001.86.4.1773.
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Although nicotinic agonists can modulate sensory transmission, particularly nociceptive signaling, remarkably little is known about the functional expression of nicotinic acetylcholine receptors (nAChRs) on primary sensory neurons. We have utilized molecular and electrophysiological techniques to characterize the functional diversity of nAChR expression on mammalian dorsal root ganglion (DRG) neurons. RT-PCR analysis of subunit mRNA in DRG tissue revealed the presence of nAChR subunits α2–7 and β2–β4. Using whole cell patch-clamp recording and rapid application of nicotinic agonists, four pharmacologically distinct categories of nicotinic responses were identified in cultured DRG neurons. Capacitance measurements were used to divide neurons into populations of large and small cells, and the prevalence of nicotinic responses was compared between groups. Category I (α7-like) responses were seen in 77% of large neurons and 32% of small neurons and were antagonized by 10 nM methyllycaconitine citrate (MLA) or or 50 nM α-bungarotoxin (α-BTX). Category II (α3β4-like) responses were seen in 16% of large neurons and 9% of small neurons and were antagonized by 20 μM mecamylamine but not 10 nM MLA or 1 μM DHβE. Category II responses had a higher sensitivity to cytisine than nicotine. Two other types of responses were identified in a much smaller percentage of neurons and were classified as either category III (α4β2-like) or category IV (subtype unknown) responses. Both the α7-like and α3β4-like responses could be desensitized by prolonged applications of the analgesic epibatidine.
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Bailey, C. D., M. K. Tian, and E. K. Lambe. "Developmental nicotine exposure and the α5 nicotinic acetylcholine receptor." Biochemical Pharmacology 82, no. 8 (October 2011): 1035. http://dx.doi.org/10.1016/j.bcp.2011.07.032.
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Wonnacott, Susan. "The paradox of nicotinic acetylcholine receptor upregulation by nicotine." Trends in Pharmacological Sciences 11, no. 6 (June 1990): 216–19. http://dx.doi.org/10.1016/0165-6147(90)90242-z.
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Smith, F. M., A. S. McGuirt, D. B. Hoover, J. A. Armour, and J. L. Ardell. "Chronic decentralization of the heart differentially remodels canine intrinsic cardiac neuron muscarinic receptors." American Journal of Physiology-Heart and Circulatory Physiology 281, no. 5 (November 1, 2001): H1919—H1930. http://dx.doi.org/10.1152/ajpheart.2001.281.5.h1919.
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The objective of the study was to determine if chronic interruption of all extrinsic nerve inputs to the heart alters cholinergic-mediated responses within the intrinsic cardiac nervous system (ICN). Extracardiac nerve inputs to the ICN were surgically interrupted (ICN decentralized). Three weeks later, the intrinsic cardiac right atrial ganglionated plexus (RAGP) was removed and intrinsic cardiac neuronal responses were evaluated electrophysiologically. Cholinergic receptor abundance was evaluated using autoradiography. In sham controls and chronic decentralized ICN ganglia, neuronal postsynaptic responses were mediated by acetylcholine, acting at nicotinic and muscarinic receptors. Muscarine- but not nicotine-mediated synaptic responses that were enhanced after chronic ICN decentralization. After chronic decentralization, muscarine facilitation of orthodromic neuronal activation increased. Receptor autoradiography demonstrated that nicotinic and muscarinic receptor density associated with the RAGP was unaffected by decentralization and that muscarinic receptors were tenfold more abundant than nicotinic receptors in the right atrial ganglia in each group. After chronic decentralization of the ICN, intrinsic cardiac neurons remain viable and responsive to cholinergic synaptic inputs. Enhanced muscarinic responsiveness of intrinsic cardiac neurons occurs without changes in receptor abundance.
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Sterz, R. K., G. Biro, K. Rajki, G. Filipp, and K. Peper. "Experimental autoimmune myasthenia gravis: can pretreatment with 125I-labeled receptor prevent functional damage at the neuromuscular junction?" Journal of Immunology 134, no. 2 (February 1, 1985): 841–46. http://dx.doi.org/10.4049/jimmunol.134.2.841.
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Abstract Rats were immunized with purified receptor from electric fish to induce experimental autoimmune myasthenia gravis (EAMG). It is implied by the clonal selection theory that antigens react only with receptors on specific immunocompetent cell subpopulations. In an attempt to damage these specific cells with the aid of highly radioactive antigen, one group of rats was pretreated with an additional injection of radiolabeled receptor of high specific activity 3 days before the basic immunization. The success of the immunization was monitored by measuring changes in the following three parameters: antibody titers against nicotinic acetylcholine receptor; number of alpha-bungarotoxin-binding sites at endplates; and number of acetylcholine-operated ionic endplate channels, using quantitative electrophysiologic methods. Conventionally immunized animals showed the classical signs of EAMG: elevated antibody titers against nicotinic acetylcholine receptor and a reduction of the number of alpha-bungarotoxin-binding sites, as well as reduction of the number of acetylcholine-operated ionic channels. The same symptoms were found in animals pretreated with unlabeled receptor and in animals pretreated with radioactive albumin. Animals pretreated with radioactively labeled receptor showed far less reduction of functional nicotinic acetylcholine receptor and only slightly raised antibody titers. This study suggests that preimmunization with radioactive antigen selectively eliminates immunocompetent cells, thus precluding the production of antibodies by a subsequent immunization procedure. The same protective effect cannot be obtained by either preimmunization with unlabeled antigen or by radioactively labeled unspecific antigen.
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Mazurov, Anatoly, Terry Hauser, and Craig Miller. "Selective α7 Nicotinic Acetylcholine Receptor Ligands." Current Medicinal Chemistry 13, no. 13 (June 1, 2006): 1567–84. http://dx.doi.org/10.2174/092986706777442011.
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Huganir, Richard L., and Kathryn Miles. "Protein Phosphorylation of Nicotinic Acetylcholine Receptor." Critical Reviews in Biochemistry and Molecular Biology 24, no. 3 (January 1989): 183–215. http://dx.doi.org/10.3109/10409238909082553.
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Miyazawa, A. "Activation mechanism of nicotinic acetylcholine receptor." Seibutsu Butsuri 43, supplement (2003): S8. http://dx.doi.org/10.2142/biophys.43.s8_3.
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WANAMAKER, CHRISTIAN P., JOHN C. CHRISTIANSON, and WILLIAM N. GREEN. "Regulation of Nicotinic Acetylcholine Receptor Assembly." Annals of the New York Academy of Sciences 998, no. 1 (September 2003): 66–80. http://dx.doi.org/10.1196/annals.1254.009.
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Tsunoyama, K., and T. Gojobori. "Evolution of nicotinic acetylcholine receptor subunits." Molecular Biology and Evolution 15, no. 5 (May 1, 1998): 518–27. http://dx.doi.org/10.1093/oxfordjournals.molbev.a025951.
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Wang, Zuo-Zhong, Stephen F. Hardy, and Zach W. Hall. "Assembly of the Nicotinic Acetylcholine Receptor." Journal of Biological Chemistry 271, no. 44 (November 1, 1996): 27575–84. http://dx.doi.org/10.1074/jbc.271.44.27575.
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Betz, H. "Nicotinic acetylcholine receptor, structure and function." Neuroscience Letters 92, no. 3 (October 1988): 352–53. http://dx.doi.org/10.1016/0304-3940(88)90617-9.
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Santanam, Nalini, Brent A. Thornhill, Jamie K. Lau, Clayton M. Crabtree, Carla R. Cook, Kathleen C. Brown, and Piyali Dasgupta. "Nicotinic acetylcholine receptor signaling in atherogenesis." Atherosclerosis 225, no. 2 (December 2012): 264–73. http://dx.doi.org/10.1016/j.atherosclerosis.2012.07.041.
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Barrantes, Francisco J. "Cholesterol effects on nicotinic acetylcholine receptor." Journal of Neurochemistry 103, s1 (November 2007): 72–80. http://dx.doi.org/10.1111/j.1471-4159.2007.04719.x.
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Wu, Jie, and Ronald J. Lukas. "Naturally-expressed nicotinic acetylcholine receptor subtypes." Biochemical Pharmacology 82, no. 8 (October 2011): 800–807. http://dx.doi.org/10.1016/j.bcp.2011.07.067.
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