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1
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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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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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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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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Dhar, S., F. Nagy, J. M. McIntosh, and H. N. Sapru. "Receptor subtypes mediating depressor responses to microinjections of nicotine into medial NTS of the rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 279, no. 1 (July 1, 2000): R132—R140. http://dx.doi.org/10.1152/ajpregu.2000.279.1.r132.
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Microinjections (50 nl) of nicotine (0.01–10 μM) into the nucleus of the solitary tract (NTS) of adult, urethan-anesthetized, artificially ventilated, male Wistar rats, elicited decreases in blood pressure and heart rate. Prior microinjections of α-bungarotoxin (α-BT) and α-conotoxin ImI (specific toxins for nicotinic receptors containing α7 subunits) elicited a 20–38% reduction in nicotine responses. Similarly, prior microinjections of hexamethonium, mecamylamine, and α-conotoxin AuIB (specific blockers or toxin for nicotinic receptors containing α3β4 subunits) elicited a 47–79% reduction in nicotine responses. Nicotine responses were completely blocked by prior sequential microinjections of α-BT and mecamylamine into the NTS. Complete blockade of excitatory amino acid receptors (EAARs) in the NTS did not attenuate the responses to nicotine. It was concluded that 1) the predominant type of nicotinic receptor in the NTS contains α3β4 subunits, 2) a smaller proportion contains α7 subunits, 3) the presynaptic nicotinic receptors in the NTS do not contribute to nicotine-induced responses, and 4) EAARs in the NTS are not involved in mediating responses to nicotine.
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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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Pinheiro, Nathalia M., Rosana Banzato, Iolanda Tibério, Marco A. M. Prado, Vânia F. Prado, Ayman K. Hamouda, and Carla M. Prado. "Acute Lung Injury in Cholinergic-Deficient Mice Supports Anti-Inflammatory Role of α7 Nicotinic Acetylcholine Receptor." International Journal of Molecular Sciences 22, no. 14 (July 14, 2021): 7552. http://dx.doi.org/10.3390/ijms22147552.
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(1) Background: The lung cholinergic pathway is important for controlling pulmonary inflammation in acute lung injury, a condition that is characterized by a sudden onset and intense inflammation. This study investigated changes in the expression levels of nicotinic and muscarinic acetylcholine receptors (nAChR and mAChR) in the lung during acute lung injury. (2) Methods: acute lung injury (ALI) was induced in wild-type and cholinergic-deficient (VAChT-KDHOM) mice using intratracheal lipopolysaccharide (LPS) instillation with or without concurrent treatment with nicotinic ligands. Bronchoalveolar lavage fluid was collected to evaluate markers of inflammation, and then the lung was removed and processed for isolation of membrane fraction and determination of acetylcholine receptors level using radioligand binding assays. (3) Results: LPS-induced increase in lung inflammatory markers (e.g., neutrophils and IL-1β) was significantly higher in VAChT-KDHOM than wild-type mice. In contrast, LPS treatment resulted in a significant increase in lung’s α7 nicotinic receptor level in wild-type, but not in VAChT-KDHOM mice. However, treatment with PNU 282987, a selective α7 nicotinic receptor agonist, restored VAChT-KDHOM mice’s ability to increase α7 nicotinic receptor levels in response to LPS-induced acute lung injury and reduced lung inflammation. LPS also increased muscarinic receptors level in VAChT-KDHOM mice, and PNU 282987 treatment reduced this response. (4) Conclusions: Our data indicate that the anti-inflammatory effects of the lung cholinergic system involve an increase in the level of α7 nicotinic receptors. Pharmacological agents that increase the expression or the function of lung α7 nicotinic receptors have potential clinical uses for treating acute lung injury.
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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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Ouchi, Yasuomi. "PET imaging of α7 nicotinic receptor." Folia Pharmacologica Japonica 145, no. 5 (2015): 266–67. http://dx.doi.org/10.1254/fpj.145.266.
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Liu, Qing-Song, and Darwin K. Berg. "Extracellular Calcium Regulates Responses of Both α3- and α7-Containing Nicotinic Receptors on Chick Ciliary Ganglion Neurons." Journal of Neurophysiology 82, no. 3 (September 1, 1999): 1124–32. http://dx.doi.org/10.1152/jn.1999.82.3.1124.
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Neuronal nicotinic receptors are generally both permeable to calcium and potentiated by it. We have examined acute calcium regulation of both native α7-containing and the less abundant α3-containing nicotinic receptors on chick ciliary ganglion neurons. Most of the receptors are concentrated on somatic spines tightly overlaid in situ by a large presynaptic calyx. Whole cell patch-clamp recording from dissociated neurons using perforated patch-clamp techniques indicates that the rapidly desensitizing nicotinic response of α7-containing receptors achieves maximum amplitude in 2 mM calcium; both lower and higher concentrations of calcium are less effective. Barium and strontium but not magnesium can substitute for calcium in potentiating the response. Neither calcium current through the receptors nor calcium action at intracellular sites is necessary. These latter conclusions are supported by current-voltage analysis of the nicotine-induced response, ion substitution experiments, and internal perfusion of the cells with 1,2-bis-(2-aminophenoxy)-ethane- N,N,N′,N′-tetraacetic acid (BAPTA) via a conventional patch pipette. Varying the agonist concentration indicates that some of the calcium-dependent enhancement may involve a shift in the dose-response curve for agonist binding, but much of the effect is also likely to involve increased receptor responsiveness. Blockade of α7-containing receptors with α-bungarotoxin showed that the heteromeric α3-containing nicotinic receptors also undergo calcium-dependent potentiation. Calcium did not have a major effect on the desensitization rate of either receptor class but did have a selective effect on the rise time of α7-containing receptors. Analysis of stably transfected cells expressing an α7 gene construct showed that the calcium potentiation observed for native receptors did not require neuron-specific modifications or components and that it could be seen with the natural agonist acetylcholine. Receptor dependence on extracellular calcium may provide a regulatory mechanism for constraining synaptic signaling, avoiding local depletion of external calcium, and limiting calcium buildup in postsynaptic compartments.
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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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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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Fu, Xiao Wen, Stephen S. Rekow, and Eliot R. Spindel. "The ly-6 protein, lynx1, is an endogenous inhibitor of nicotinic signaling in airway epithelium." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 8 (October 15, 2012): L661—L668. http://dx.doi.org/10.1152/ajplung.00075.2012.
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Our laboratory has previously reported that bronchial epithelial cells (BEC) express a regulatory cascade of classic neurotransmitters and receptors that communicate in an almost neuronal-like manner to achieve physiological regulation. In this paper we show that the similarity between neurotransmitter signaling in neurons and BEC extends to the level of transmitter receptor allosteric modulators. Lynx1 is a member of the ly-6/three-finger superfamily of proteins, many of which modulate receptor signaling activity. Lynx1 specifically has been shown to modulate nicotinic acetylcholine receptor (nAChR) function in neurons by altering receptor sensitivity and desensitization. We now report that lynx1 forms a complex with α7 nAChR in BEC and serves to negatively regulate α7 downstream signaling events. Treatment of primary cultures of BEC with nicotine increased levels of nAChR subunits and that increase was potentiated by lynx1 knockdown. Lynx1 knockdown also potentiated the nicotine-induced increase in GABAA receptors (GABAAR) and MUC5AC mRNA expression, and that effect was blocked by α7 antagonists and α7 knockdown. In parallel with the increases in nAChR, GABAAR, and mucin mRNA levels, lynx1 knockdown also increased levels of p-Src. Consistent with this, inhibition of Src signaling blocked the ability of the lynx1 knockdown to increase basal and nicotine-stimulated GABAAR and mucin mRNA expression. Thus lynx1 appears to act as a negative modulator of α7 nAChR-induced events by inhibiting Src activation. This suggests that lynx1 agonists or mimetics are a potentially important therapeutic target to develop new therapies for smoking-related diseases characterized by increased mucin expression.
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Liu, Danlin, João V. de Souza, Ayaz Ahmad, and Agnieszka K. Bronowska. "Structure, Dynamics, and Ligand Recognition of Human-Specific CHRFAM7A (Dupα7) Nicotinic Receptor Linked to Neuropsychiatric Disorders." International Journal of Molecular Sciences 22, no. 11 (May 22, 2021): 5466. http://dx.doi.org/10.3390/ijms22115466.
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Cholinergic α7 nicotinic receptors encoded by the CHRNA7 gene are ligand-gated ion channels directly related to memory and immunomodulation. Exons 5–7 in CHRNA7 can be duplicated and fused to exons A-E of FAR7a, resulting in a hybrid gene known as CHRFAM7A, unique to humans. Its product, denoted herein as Dupα7, is a truncated subunit where the N-terminal 146 residues of the ligand binding domain of the α7 receptor have been replaced by 27 residues from FAM7. Dupα7 negatively affects the functioning of α7 receptors associated with neurological disorders, including Alzheimer’s diseases and schizophrenia. However, the stoichiometry for the α7 nicotinic receptor containing dupα7 monomers remains unknown. In this work, we developed computational models of all possible combinations of wild-type α7 and dupα7 pentamers and evaluated their stability via atomistic molecular dynamics and coarse-grain simulations. We assessed the effect of dupα7 subunits on the Ca2+ conductance using free energy calculations. We showed that receptors comprising of four or more dupα7 subunits are not stable enough to constitute a functional ion channel. We also showed that models with dupα7/α7 interfaces are more stable and are less detrimental for the ion conductance in comparison to dupα7/dupα7 interfaces. Based on these models, we used protein–protein docking to evaluate how such interfaces would interact with an antagonist, α-bungarotoxin, and amyloid Aβ42. Our findings show that the optimal stoichiometry of dupα7/α7 functional pentamers should be no more than three dupα7 monomers, in favour of a dupα7/α7 interface in comparison to a homodimer dupα7/dupα7 interface. We also showed that receptors bearing dupα7 subunits are less sensitive to Aβ42 effects, which may shed light on the translational gap reported for strategies focused on nicotinic receptors in ‘Alzheimer’s disease research.
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Alkondon, Manickavasagom, and Edson X. Albuquerque. "A Non-α7 Nicotinic Acetylcholine Receptor Modulates Excitatory Input to Hippocampal CA1 Interneurons." Journal of Neurophysiology 87, no. 3 (March 1, 2002): 1651–54. http://dx.doi.org/10.1152/jn.00708.2001.
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The nicotinic acetylcholine receptor (nAChR), particularly the α7 subtype, has received profound attention for its role in modifying excitatory postsynaptic currents (EPSCs) in hippocampal pyramidal neurons as well as in neurons from other brain regions. Here, we tested the possibility that an nAChR could affect EPSCs in the interneurons of rat hippocampal slices. Using whole-cell patch-clamp technique on CA1 stratum radiatum interneurons and U-tube application of agents, we show that nicotinic agonists enhance EPSC frequency in interneurons. Among the agents tested, cytisine and mecamylamine were the most effective agonist and antagonist, respectively, suggesting a role for α3β4-containing nAChRs in the modulation of interneuron EPSCs. Ligands selective for the α7 nAChR had very little or no effect on interneuron EPSCs. Low concentrations of nicotine also enhanced EPSC frequency, implicating the involvement of non-α7 nAChRs in controlling interneuron excitability in smokers. We conclude that nAChR-dependent EPSC modulation in the hippocampus is both subtype- and neuron-specific and that a non-α7 nAChR, presumably α3β4, controls glutamate transmission to CA1 interneurons.
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Garg, Brijesh K., and Ralph H. Loring. "Evaluating Commercially Available Antibodies for Rat α7 Nicotinic Acetylcholine Receptors." Journal of Histochemistry & Cytochemistry 65, no. 9 (August 1, 2017): 499–512. http://dx.doi.org/10.1369/0022155417725304.
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Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) are important drug targets in neurological disorders and inflammation, making their detection and localization by validated antibodies highly desirable. However, tests in knockout animals raised questions about specificity of antibodies to mouse α7 nAChRs. To date, methods for validating antibodies for rat or human α7 nAChR have not been reported. We developed a gel-shift assay for western blots using GH4C1 cells expressing either native rat receptors or α7 nAChR-green fluorescent protein (GFP) chimeras to evaluate seven commercially available α7 nAChR antibodies. Blots with anti-GFP antibody detected GFP or α7 nAChR-GFP expressed in GH4C1 cells, and 125I-α-bungarotoxin binding and RNA analysis demonstrated α7 nAChR expression. Validated samples were used to evaluate α7 nAChR antibodies by western blot and immunofluorescence studies. These methods confirmed that two of seven α7 nAChR antibodies identify gel-shifts for α7 nAChR/nAChR-GFP but only one antibody demonstrated low background and significant immunofluorescence differences between wild-type and α7 nAChR expressing GH4C1 cells. However, that polyclonal antibody displayed lot-to-lot variability. Our findings suggest that careful validation methods are required for all α7 nAChR receptor species and antibody lots and that the gel-shift assay may allow for relatively rapid antibody screening.
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Cortés, Magdalena P., Rocío Alvarez, Evelyn Sepúlveda, Felipe Jiménez-Aspee, Luis Astudillo, Gabriel Vallejos, and Margarita Gutiérrez. "A New Isoxazolic Compound Acts as α7 Nicotinic Receptor Agonist in Human Umbilical Vein Endothelial Cells." Zeitschrift für Naturforschung C 69, no. 7-8 (August 1, 2014): 291–99. http://dx.doi.org/10.5560/znc.2012-0176.
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Recent evidence suggests that the α7 nicotinic acetylcholine receptors (α7 nAChRs) participate in the development of angiogenesis and could be a new endothelial target for revascularization in therapeutic angiogenesis. It has been shown that in human umbilical vein endothelial cells (HUVECs) α7 nAChR agonists increase the intracellular calcium concentration ([Ca2+]i), thus inducing proliferation and vessel formation which are important stages of angiogenesis. In the present study we evaluated the effect of new isoxazole compounds on the cytosolic Ca2+ signal in HUVECs using the fluorescent Ca2+ indicator Fluo-3AM and probing the involvement of α7 nAChR by means of pharmacological tools. HUVECs expressed mainly α7 nAChR, since there was no significant difference in the increase in [Ca2+]i induced by nicotine, a non-selective nicotinic agonist, in relation to choline, a selective α7 nAChR agonist. The increase in [Ca2+]i induced by 1 mM choline was inhibited significantly (p = 0.014) in cells which had been pre-incubated for 15 min with methyllycaconitine (MLA), a selective α7 nAChR antagonist. The studied compounds 1, 2, and 3 induced an increase in [Ca2+]i in a dose-dependent manner. Compound 1 at 10 mM induced a greater increase in [Ca2+]i than compounds 2 and 3. The increase in [Ca2+]i induced by compound 1 was significantly inhibited by MLA (p = 0.013) and completely inhibited by mecamylamine, a non-selective nAChR antagonist, indicating that the isoxazolic compound 1 acts as an α7 nAChR agonist.
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Arredondo, Juan, Vu Thuong Nguyen, Alexander I. Chernyavsky, Dani Bercovich, Avi Orr-Urtreger, Wolfgang Kummer, Katrin Lips, Douglas E. Vetter, and Sergei A. Grando. "Central role of α7 nicotinic receptor in differentiation of the stratified squamous epithelium." Journal of Cell Biology 159, no. 2 (October 21, 2002): 325–36. http://dx.doi.org/10.1083/jcb.200206096.
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Several ganglionic nicotinic acetylcholine receptor (nAChR) types are abundantly expressed in nonneuronal locations, but their functions remain unknown. We found that keratinocyte α7 nAChR controls homeostasis and terminal differentiation of epidermal keratinocytes required for formation of the skin barrier. The effects of functional inactivation of α7 nAChR on keratinocyte cell cycle progression, differentiation, and apoptosis were studied in cell monolayers treated with α-bungarotoxin or antisense oligonucleotides and in the skin of Acra7 homozygous mice lacking α7 nAChR channels. Elimination of the α7 signaling pathway blocked nicotine-induced influx of 45Ca2+ and also inhibited terminal differentiation of these cells at the transcriptional and/or translational level. On the other hand, inhibition of the α7 nAChR pathway favored cell cycle progression. In the epidermis of α7−/− mice, the abnormalities in keratinocyte gene expression were associated with phenotypic changes characteristic of delayed epidermal turnover. The lack of α7 was associated with up-regulated expression of the α3 containing nAChR channels that lack α5 subunit, and both homomeric α9- and heteromeric α9α10-made nAChRs. Thus, this study demonstrates that ACh signaling through α7 nAChR channels controls late stages of keratinocyte development in the epidermis by regulating expression of the cell cycle progression, apoptosis, and terminal differentiation genes and that these effects are mediated, at least in part, by alterations in transmembrane Ca2+ influx.
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Potasiewicz, Agnieszka, Joanna Golebiowska, Piotr Popik, and Agnieszka Nikiforuk. "Procognitive effects of varenicline in the animal model of schizophrenia depend on α4β2- and α7-nicotinic acetylcholine receptors." Journal of Psychopharmacology 33, no. 1 (December 3, 2018): 62–73. http://dx.doi.org/10.1177/0269881118812097.
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Background: Varenicline, a partial agonist of the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR), is currently used to facilitate smoking cessation. Preclinical and clinical studies have suggested that this compound may also be effective in treating cognitive impairments in schizophrenia. However, it is unclear which nicotinic acetylcholine receptor subtypes may be involved because varenicline is not only a partial agonist for α4β2-nAChRs but also a full agonist for α7 nicotinic acetylcholine receptors (α7-nAChRs). Aim: We investigated the effects of varenicline, compared to the α4β2-nAChR partial agonist TC-2403 and the α7-nAChR full agonist PNU-282987, in a ketamine-based model of schizophrenia-like cognitive deficits on the attentional set-shifting task in rats. The second goal was to elucidate whether the procognitive efficacy of varenicline was due to the compound’s action on α4β2-nAChRs or α7-nAChRs. Methods: Ketamine was administered to rats for 10 consecutive days and the test was performed 14 days following the last injection. The tested compounds were administered 30 min prior to the attentional set-shifting task. Results: Varenicline, TC-2403 and PNU-282987 ameliorated ketamine-evoked set-shifting deficits. While the α4β2-nAChR antagonist dihydro-β-erythroidine and the α7-nAChR antagonist methyllycaconitine completely prevented the procognitive actions of TC-2403 and PNU-282987, respectively, varenicline’s effect was only partially blocked by any given antagonist. Moreover, the combined treatment with TC-2403 and PNU-282987 more effectively facilitated rats’ set-shifting ability than activation of either type of nicotinic acetylcholine receptor alone. Conclusion: The present findings demonstrated that varenicline’s actions on both α7-nAChRs and α4β2-nAChRs may be necessary to produce its full procognitive effect in the present experimental setting.
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Rezonzew, Gabriel, Phillip Chumley, Wenguang Feng, Ping Hua, Gene P. Siegal, and Edgar A. Jaimes. "Nicotine exposure and the progression of chronic kidney disease: role of the α7-nicotinic acetylcholine receptor." American Journal of Physiology-Renal Physiology 303, no. 2 (July 15, 2012): F304—F312. http://dx.doi.org/10.1152/ajprenal.00661.2011.
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Clinical studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease (CKD). We have shown that nicotine promotes mesangial cell proliferation and hypertrophy via nonneuronal nicotinic acetylcholine receptors (nAChRs). The α7-nAChR is one of the most important subunits of the nAChRs. These studies were designed to test the hypothesis that nicotine worsens renal injury in rats with 5/6 nephrectomy (5/6Nx) and that the α7-nAChR subunit is required for these effects. We studied five different groups: Sham, 5/6Nx, 5/6Nx + nicotine (Nic; 100 μg/ml dry wt), 5/6Nx + Nic + α7-nAChR blocker methyllicaconitine (MLA; 3 mg·kg−1·day−1 sq), and Sham + Nic. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. After 12 wk, the rats were euthanized and kidneys were collected. We observed expression of the α7-nAChR in the proximal and distal tubules. The administration of nicotine induced a small increase in blood pressure and resulted in cotinine levels similar to those found in the plasma of smokers. In 5/6Nx rats, the administration of nicotine significantly increased urinary protein excretion (onefold), worsened the glomerular injury score and increased fibronectin (∼ 50%), NADPH oxidase 4 (NOX4; ∼100%), and transforming growth factor-β expression (∼200%). The administration of nicotine to sham rats increased total proteinuria but not albuminuria, suggesting direct effects on tubular protein reabsorption. These effects were prevented by MLA, demonstrating a critical role for the α7-nAChR as a mediator of the effects of nicotine in the progression of CKD.
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Lykhmus, Olena, Olena Kalashnyk, Kateryna Uspenska, Tetyana Horid’ko, Halyna Kosyakova, Serhiy Komisarenko, and Maryna Skok. "Different Effects of Nicotine and N-Stearoyl-ethanolamine on Episodic Memory and Brain Mitochondria of α7 Nicotinic Acetylcholine Receptor Knockout Mice." Biomolecules 10, no. 2 (February 3, 2020): 226. http://dx.doi.org/10.3390/biom10020226.
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Nicotinic acetylcholine receptors of α7 subtype (α7 nAChRs) are involved in regulating neuroinflammation and cognitive functions. Correspondingly, α7-/- mice demonstrate pro-inflammatory phenotype and impaired episodic memory. In addition, nAChRs expressed in mitochondria regulate the release of pro-apoptotic factors like cytochrome c. Here we studied whether the cognitive deficiency of α7-/- mice can be cured by oral consumption of either nicotine or N-stearoylethanolamine (NSE), a lipid possessing anti-inflammatory, cannabimimetic and membrane-stabilizing activity. Mice were examined in Novel Object Recognition behavioral test, their blood, brains and brain mitochondria were tested for the levels of interleukin-6, various nAChR subtypes and cytochrome c released by ELISA. The data presented demonstrate that both substances stimulated the raise of interleukin-6 in the blood and improved episodic memory of α7-/- mice. However, NSE improved, while nicotine worsened the brain mitochondria sustainability to apoptogenic stimuli, as shown by either decreased or increased amounts of cytochrome c released. Both nicotine and NSE up-regulated α4β2 nAChRs in the brain; NSE up-regulated, while nicotine down-regulated α9-containing nAChRs in the brain mitochondria. It is concluded that the level of alternative nAChR subtypes in the brain is critically important for memory and mitochondria sustainability in the absence of α7 nAChRs.
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Uteshev, Vladimir V., Edwin M. Meyer, and Roger L. Papke. "Regulation of Neuronal Function by Choline and 4OH-GTS-21 Through α7 Nicotinic Receptors." Journal of Neurophysiology 89, no. 4 (April 1, 2003): 1797–806. http://dx.doi.org/10.1152/jn.00943.2002.
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A unique feature of α7 nicotinic acetylcholine receptor physiology is that, under normal physiological conditions, α7 receptors are constantly perfused with their natural selective agonist, choline. Studying neurons of hypothalamic tuberomammillary (TM) nucleus, we show that choline and the selective α7 receptor agonist 4OH-GTS-21 can regulate neuronal functions directly, via activation of the native α7 receptors, and indirectly, via desensitizing those receptors or transferring them into a state “primed” for desensitization. The direct action produces depolarization and thereby increases the TM neuron spontaneous firing (SF) rate. The regulation of the spontaneous firing rate is robust in a nonphysiological range of choline concentrations >200 μM. However, modest effects persist at concentrations of choline that are likely to be attained perineuronally under some conditions (20–100 μM). At high physiological concentration levels, the indirect choline action reduces or even eliminates the responsiveness of α7 receptors and their availability to other strong cholinergic inputs. Similarly to choline, 4OH-GTS-21 increases the TM neuron spontaneous firing rate via activation of α7 receptors, and this regulation is robust in the range of clinically relevant concentrations of 4OH-GTS-21. We conclude that factors that regulate choline accumulation in the brain and in experimental slices such as choline uptake, hydrolysis of ACh, membrane phosphatidylcholine catabolism, and solution perfusion rate influence α7 nAChR neuronal and synaptic functions, especially under pathological conditions such as stroke, seizures, Alzheimer's disease, and head trauma, when the choline concentration in the CSF is expected to rise.
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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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Ren, Zhenkui, Mei Yang, Zhizhong Guan, and Wenfeng Yu. "Astrocytic α7 Nicotinic Receptor Activation Inhibits Amyloid-β Aggregation by Upregulating Endogenous αB-crystallin through the PI3K/Akt Signaling Pathway." Current Alzheimer Research 16, no. 1 (December 31, 2018): 39–48. http://dx.doi.org/10.2174/1567205015666181022093359.
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Background: β-amyloid (Aβ) aggregation plays an important role in the pathogenesis of Alzheimer’s disease (AD), and astrocytes can significantly inhibit Aβ aggregation. Astrocytic α7 Neuronal Nicotinic Acetylcholine Receptor (nAChR) upregulation detected in the AD brains is closely associated with Aβ deposits. However, the relationships between the astrocytic α7 nAChRs and Aβ aggregation remain unclear. Methods: The Aβ oligomers levels in astrocytic cell lysates and culture medium were measured after treatment with nicotine or co-treatment with a Phosphatidylinositol 3-Kinase (PI3K)-protein kinase B (Akt) inhibitor. The level of αB-Crystallin (Cryab) in astrocytes treated with nicotine for different times or co-treated with α7 nAChR antagonists as well as co-incubated with a PI3K or mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was determined by western blotting. Results: In this study, nicotine pre-treatment in primary astrocytes markedly inhibited Aβ aggregation and upregulated endogenous astrocytic Cryab, while the nicotine-mediated neuroprotective effect was reversed by pre-treatment with a selective α7 nAChR antagonist. Furthermore, this neuroprotection against Aβ aggregation was suppressed by LY294002, a PI3K inhibitor. Pre-treatment with nicotine significantly increased the levels of phosphorylated Akt, an effector of PI3K in astrocytes. Conclusion: α7 nAChR activation and PI3K/Akt signaling transduction contributed to nicotinemediated neuroprotection against Aβ aggregation by modulating endogenous astrocytic Cryab.
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Lam, David Chi-Leung, Susan Yang Luo, Kin-Hang Fu, Macy Mei-Sze Lui, Koon-Ho Chan, Ignacio Ivans Wistuba, Boning Gao, Sai-Wah Tsao, Mary Sau-Man Ip, and John Dorrance Minna. "Nicotinic acetylcholine receptor expression in human airway correlates with lung function." American Journal of Physiology-Lung Cellular and Molecular Physiology 310, no. 3 (February 1, 2016): L232—L239. http://dx.doi.org/10.1152/ajplung.00101.2015.
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Nicotine and its derivatives, by binding to nicotinic acetylcholine receptors ( nAChRs) on bronchial epithelial cells, can regulate cellular signaling and inflammatory processes. Delineation of nAChR subtypes and their responses to nicotine stimulation in bronchial epithelium may provide information for therapeutic targeting in smoking-related inflammation in the airway. Expression of nAChR subunit genes in 60 bronchial epithelial biopsies and immunohistochemical staining for the subcellular locations of nAChR subunit expression were evaluated. Seven human bronchial epithelial cell lines (HBECs) were exposed to nicotine in vitro for their response in nAChR subunit gene expression to nicotine exposure and removal. The relative normalized amount of expression of nAChR α4, α5, and α7 and immunohistochemical staining intensity of nAChR α4, α5, and β3 expression showed significant correlation with lung function parameters. Nicotine stimulation in HBECs resulted in transient increase in the levels of nAChR α5 and α6 but more sustained increase in nAChR α7 expression. nAChR expression in bronchial epithelium was found to correlate with lung function. Nicotine exposure in HBECs resulted in both short and longer term responses in nAChR subunit gene expression. These results gave insight into the potential of targeting nAChRs for therapy in smoking-related inflammation in the airway.
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Ryan, R. E., and R. E. Loiacono. "Nicotine regulates α7 nicotinic receptor subunit mRNA: implications for nicotine dependence." Neuroreport 12, no. 3 (March 2001): 569–72. http://dx.doi.org/10.1097/00001756-200103050-00027.
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Fu, Wen, and Jack H. Jhamandas. "β-Amyloid Peptide Activates Non-α7 Nicotinic Acetylcholine Receptors in Rat Basal Forebrain Neurons." Journal of Neurophysiology 90, no. 5 (November 2003): 3130–36. http://dx.doi.org/10.1152/jn.00616.2003.
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Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by profound deficits in memory and cognitive function. Neuropathological hallmarks of the disease include a loss of basal forebrain cholinergic neurons and the deposition of β-amyloid peptide (Aβ) in neuritic plaques. At a cellular level, considerable attention has focused on a study of Aβ interactions with the neuronal nicotinic acetylcholine receptor (nAChR) subtypes. In this study, using cell-attached and outside-out single channel recordings from acutely dissociated rat basal forebrain neurons, we report that Aβ and nicotine activate nAChRs with two distinct levels of single-channel conductance. Whole cell recordings from these neurons reveal Aβ and nicotine, in a concentration-dependent and reversible manner, evoke brisk depolarizing responses and an inward current. The effects of Aβ on both single channel and whole cell are blocked by the noncompetitive nAChR antagonist mecamylamine and competitive nAChR antagonist dihydro-beta-erythroidine, but not the specific α7-selective nAChR antagonist methyllycaconitine, indicating that Aβ activated non-α7 nAChRs on basal forebrain neurons. In addition, the non-α7 nAChR agonists UB-165, epibatidine, and cytisine, but not the selective α7 agonist AR-R17779, induced similar responses as Aβ and nicotine. Thus non-α7 nAChRs may also represent a novel target in mediating the effects of Aβ in AD.
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Dunlop, John, Ravikumar Peri, Georg C. Terstappen, and Mark Bowlby. "Functional screening of α7 nicotinic receptor ligands." Expert Opinion on Drug Discovery 3, no. 6 (May 22, 2008): 623–28. http://dx.doi.org/10.1517/17460441.3.6.623.
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Ekins, Sean, Paul Mathews, Erin K. Saito, Natalie Diaz, David Naylor, Julia Chung, and Aaron M. McMurtray. "α7-Nicotinic acetylcholine receptor inhibition by indinavir." AIDS 31, no. 8 (May 2017): 1083–89. http://dx.doi.org/10.1097/qad.0000000000001488.
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Peng, Youyi, Qiang Zhang, Gretchen L. Snyder, Hongwen Zhu, Wei Yao, John Tomesch, Roger L. Papke, James P. O’Callaghan, William J. Welsh, and Lawrence P. Wennogle. "Discovery of novel α7 nicotinic receptor antagonists." Bioorganic & Medicinal Chemistry Letters 20, no. 16 (August 2010): 4825–30. http://dx.doi.org/10.1016/j.bmcl.2010.06.103.
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Stolerman, I. P., S. Chamberlain, L. Bizarro, C. Fernandes, and L. Schalkwyk. "The role of nicotinic receptor α7 subunits in nicotine discrimination." Neuropharmacology 46, no. 3 (March 2004): 363–71. http://dx.doi.org/10.1016/j.neuropharm.2003.10.002.
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Gausserès, Blandine, Junjun Liu, Ewout Foppen, Cécile Tourrel-Cuzin, Ana Rodriguez Sanchez-Archidona, Etienne Delangre, Céline Cruciani-Guglielmacci, et al. "The Constitutive Lack of α7 Nicotinic Receptor Leads to Metabolic Disorders in Mouse." Biomolecules 10, no. 7 (July 16, 2020): 1057. http://dx.doi.org/10.3390/biom10071057.
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Objective: Type 2 diabetes (T2D) occurs by deterioration in pancreatic β-cell function and/or progressive loss of pancreatic β-cell mass under the context of insulin resistance. α7 nicotinic acetylcholine receptor (nAChR) may contribute to insulin sensitivity but its role in the pathogenesis of T2D remains undefined. We investigated whether the systemic lack of α7 nAChR was sufficient to impair glucose homeostasis. Methods: We used an α7 nAChR knock-out (α7−/−) mouse model fed a standard chow diet. The effects of the lack of α7 nAChR on islet mass, insulin secretion, glucose and insulin tolerance, body composition, and food behaviour were assessed in vivo and ex vivo experiments. Results: Young α7−/− mice display a chronic mild high glycemia combined with an impaired glucose tolerance and a marked deficit in β-cell mass. In addition to these metabolic disorders, old mice developed adipose tissue inflammation, elevated plasma free fatty acid concentrations and presented glycolytic muscle insulin resistance in old mice. Finally, α7−/− mice, fed a chow diet, exhibited a late-onset excessive gain in body weight through increased fat mass associated with higher food intake. Conclusion: Our work highlights the important role of α7 nAChR in glucose homeostasis. The constitutive lack of α7 nAChR suggests a novel pathway influencing the pathogenesis of T2D.
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Huang, Zheng-Gui, Xin Wang, Cory Evans, Allison Gold, Evguenia Bouairi, and David Mendelowitz. "Prenatal Nicotine Exposure Alters the Types of Nicotinic Receptors That Facilitate Excitatory Inputs to Cardiac Vagal Neurons." Journal of Neurophysiology 92, no. 4 (October 2004): 2548–54. http://dx.doi.org/10.1152/jn.00500.2004.
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Nicotinic receptors play an important role in modulating the activity of parasympathetic cardiac vagal neurons in the medulla. Previous work has shown nicotine acts via at least three mechanisms to excite brain stem premotor cardiac vagal neurons. Nicotine evokes a direct increase in holding current and facilitates both the frequency and amplitude of glutamatergic neurotransmission to cardiac vagal neurons. This study tests whether these nicotinic receptor–mediated responses are endogenously active, whether α4β2 and α7 nicotinic receptors are involved, and whether prenatal exposure to nicotine alters the magnitude of these responses and the types of nicotinic receptors involved. Application of neostigmine (10 μM) significantly increased the holding current, amplitude, and frequency of miniature excitatory postsynaptic current (mEPSC) glutamatergic events in cardiac vagal neurons. In unexposed animals, the nicotine-evoked facilitation of mEPSC frequency, but not mEPSC amplitude or holding current, was blocked by α-bungarotoxin (100 nM). Prenatal nicotine exposure significantly exaggerated and altered the types of nicotinic receptors involved in these responses. In prenatal nicotine-exposed animals, α-bungarotoxin only partially reduced the increase in mEPSC frequency. In addition, in prenatal nicotine-exposed animals, the increase in holding current was partially dependent on α-7 subunit–containing nicotinic receptors, in contrast to unexposed animals in which α-bungarotoxin had no effect. These results indicate prenatal nicotine exposure, one of the highest risk factors for sudden infant death syndrome (SIDS), exaggerates the responses and changes the types of nicotinic receptors involved in exciting premotor cardiac vagal neurons. These alterations could be responsible for the pronounced bradycardia that occurs during apnea in SIDS victims.
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Hajiasgharzadeh, Khalil, Mohammad Hossein Somi, Behzad Mansoori, Mohammad Amin Doustvandi, Fatemeh Vahidian, Mohsen Alizadeh, Ahad Mokhtarzadeh, Dariush Shanehbandi, and Behzad Baradaran. "Alpha7 Nicotinic Acetylcholine Receptor Mediates Nicotine-induced Apoptosis and Cell Cycle Arrest of Hepatocellular Carcinoma HepG2 Cells." Advanced Pharmaceutical Bulletin 10, no. 1 (December 11, 2019): 65–71. http://dx.doi.org/10.15171/apb.2020.008.
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Purpose: The cytotoxic properties upon treatment with nicotine have been reported in several studies, but the underlying mechanisms remain not fully defined. The alpha7 nicotinic acetylcholine receptor (α7nAChR) is one of the important nicotinic receptors, which nicotine partly by binding to this receptor exerts its effects. The current study aimed to investigates the influences of nicotine on cellular proliferative and apoptotic activities and tried to determine the involvement of α7nAChR in these functions. Methods: Human hepatocellular carcinoma (HepG2) cell line was used to determine the individual or combined effects of treatments with nicotine (10 μM) and specific siRNA (100 nM) targeting α7nAChR expression. The MTT assay, DAPI staining assay, and flow cytometry assay were applied to measure the cell viability, apoptosis and cell cycle progression of the cells, respectively. In addition, the changes in the mRNA level of the genes were assessed by qRT-PCR. Results: Compared to control groups, the cells treated with nicotine exhibited significant dosedependent decreases in cell viability (log IC50 = -5.12±0.15). Furthermore, nicotine induced apoptosis and cell cycle arrest especially at G2/M Phase. The qRT-PCR revealed that nicotine increased the mRNA levels of α7nAChR as well as caspase-3 and suppressed the expression of cyclin B1. Treatment with α7-siRNA abolished these effects of nicotine. Conclusion: These experiments determined that upregulation of α7nAChR by nicotine inhibits HepG2 cells proliferation and induces their apoptosis. These effects blocked by treatment with α7-siRNA, which indicates the involvement of α7nAChR pathways in these processes.
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Alkondon, Manickavasagom, Edna F. R. Pereira, and Edson X. Albuquerque. "NMDA and AMPA Receptors Contribute to the Nicotinic Cholinergic Excitation of CA1 Interneurons in the Rat Hippocampus." Journal of Neurophysiology 90, no. 3 (September 2003): 1613–25. http://dx.doi.org/10.1152/jn.00214.2003.
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In the hippocampus, glutamatergic inputs to pyramidal neurons and interneurons are modulated by α7* and α3β4* nicotinic acetylcholine receptors (nAChRs), respectively, present in glutamatergic neurons. This study examines how nicotinic AMPA, and NMDA receptor nAChR activities are integrated to regulate the excitability of CA1 stratum radiatum (SR) interneurons in rat hippocampal slices. At resting membrane potentials and in the presence of extracellular Mg2+ (1 mM), nicotinic agonists triggered in SR interneurons excitatory postsynaptic currents (EPSCs) that had two components: one mediated by AMPA receptors, and the other by NMDA receptors. As previously shown, nicotinic agonist–triggered EPSCs resulted from glutamate released by activation of α3β4* nAChRs in glutamatergic neurons/fibers synapsing directly onto the neurons under study. The finding that CNQX caused more inhibition of nicotinic agonist–triggered EPSCs than expected from the blockade of postsynaptic AMPA receptors indicated that this nicotinic response also depended on the AMPA receptor activity in the glutamatergic neurons synapsing onto the interneuron under study. Nicotinic agonists always triggered action potentials in CA1 SR interneurons. In most interneurons, these action potentials resulted from activation of somatodendritic AMPA receptors and α7* nAChRs. In interneurons expressing somatodendritic α4β2* nAChRs, activation of these receptors caused sufficient membrane depolarization to remove the Mg2+-induced block of somatodendritic NMDA receptors; in these neurons, nicotinic agonist–triggered action potentials were partially dependent on NMDA receptor activation. Removing extracellular Mg2+ or clamping the neuron at positive membrane potentials revealed the existence of a tonic NMDA current in SR interneurons that was unaffected by nAChR activation or inhibition. Thus integration of the activities of nAChRs, NMDA, and AMPA receptors in different compartments of CA1 neurons contributes to the excitability of CA1 SR interneurons.
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Piovesana, Roberta, Michael Sebastian Salazar Intriago, Luciana Dini, and Ada Maria Tata. "Cholinergic Modulation of Neuroinflammation: Focus on α7 Nicotinic Receptor." International Journal of Molecular Sciences 22, no. 9 (May 6, 2021): 4912. http://dx.doi.org/10.3390/ijms22094912.
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All nervous system pathologies (e.g., neurodegenerative/demyelinating diseases and brain tumours) develop neuroinflammation, a beneficial process during pathological events, aimed at removing damaged cells, toxic agents, and/or pathogens. Unfortunately, excessive inflammation frequently occurs during nervous system disorders, becoming a detrimental event capable of enhancing neurons and myelinating glial cell impairment, rather than improving their survival and activity. Consequently, targeting the neuroinflammation could be relevant for reducing brain injury and rescuing neuronal and glial cell functions. Several studies have highlighted the role of acetylcholine and its receptors in the regulation of central and peripheral inflammation. In particular, α7 nicotinic receptor has been described as one of the main regulators of the “brain cholinergic anti-inflammatory pathway”. Its expression in astrocytes and microglial cells and the ability to modulate anti-inflammatory cytokines make this receptor a new interesting therapeutic target for neuroinflammation regulation. In this review, we summarize the distribution and physiological functions of the α7 nicotinic receptor in glial cells (astrocytes and microglia) and its role in the modulation of neuroinflammation. Moreover, we explore how its altered expression and function contribute to the development of different neurological pathologies and exacerbate neuroinflammatory processes.
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Gahring, Lorise C., Elizabeth J. Myers, Diane M. Dunn, Robert B. Weiss, and Scott W. Rogers. "Lung eosinophilia induced by house dust mites or ovalbumin is modulated by nicotinic receptor α7 and inhibited by cigarette smoke." American Journal of Physiology-Lung Cellular and Molecular Physiology 315, no. 4 (October 1, 2018): L553—L562. http://dx.doi.org/10.1152/ajplung.00230.2018.
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Eosinophilia (EOS) is an important component of airway inflammation and hyperresponsiveness in allergic reactions including those leading to asthma. Although cigarette smoking (CS) is a significant contributor to long-term adverse outcomes in these lung disorders, there are also the curious reports of its ability to produce acute suppression of inflammatory responses including EOS through poorly understood mechanisms. One possibility is that proinflammatory processes are suppressed by nicotine in CS acting through nicotinic receptor α7 (α7). Here we addressed the role of α7 in modulating EOS with two mouse models of an allergic response: house dust mites (HDM; Dermatophagoides sp.) and ovalbumin (OVA). The influence of α7 on EOS was experimentally resolved in wild-type mice or in mice in which a point mutation of the α7 receptor (α7E260A:G) selectively restricts normal signaling of cellular responses. RNA analysis of alveolar macrophages and the distal lung epithelium indicates that normal α7 function robustly impacts gene expression in the epithelium to HDM and OVA but to different degrees. Notable was allergen-specific α7 modulation of Ccl11 and Ccl24 (eotaxins) expression, which was enhanced in HDM but suppressed in OVA EOS. CS suppressed EOS induced by both OVA and HDM, as well as the inflammatory genes involved, regardless of α7 genotype. These results suggest that EOS in response to HDM or OVA is through signaling pathways that are modulated in a cell-specific manner by α7 and are distinct from CS suppression.
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Sooksawate, Thongchai, Kaoru Isa, and Tadashi Isa. "Cholinergic Responses in Crossed Tecto-Reticular Neurons of Rat Superior Colliculus." Journal of Neurophysiology 100, no. 5 (November 2008): 2702–11. http://dx.doi.org/10.1152/jn.90723.2008.
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Neurons in the intermediate gray layer (SGI) of mammalian superior colliculus (SC) receive cholinergic innervation from the brain stem parabrachial region, which seems to modulate the signal processing in the SC. To clarify its role particularly in orienting behaviors, we studied cholinergic effects on the major output neuron group of the SGI, crossed tecto-reticular neurons (cTRNs), identified by retrograde labeling from the contralateral brain stem gaze center in SC slices obtained from rats (PND 17–22) by whole cell patch-clamp techniques. Bath application of carbachol induced either 1) nicotinic inward (nIN) + muscarinic inward (mIN) (11/24) or 2) nIN + mIN + muscarinic outward (mOUT) (13/24) current responses. Transient pressure application of 1 mM acetylcholine elicited nIN in all neurons tested ( n = 58). In a majority of these neurons (52/58), the nIN was completely suppressed by dihydro-β-erythroidine, a specific antagonist for α4β2 nicotinic receptor subtype. The remaining 6/58 neurons exhibited not only the slower α4β2 receptor-mediated component but also a faster component that was inhibited by a specific antagonist for α7 nicotinic receptor, α-bungarotoxin. cTRNs expressing α7 nicotinic receptors tended to be smaller in size than those lacking α7 receptors. Bath application of muscarine induced two response patterns: mIN only (17/38) and mIN+ mOUT (21/38). The mIN and mOUT were mediated by M3 (plus M1) and M2 muscarinic receptors, respectively. These results suggest that a major response to cholinergic inputs to cTRNs is excitatory. This would indicate the facilitatory role of the brain stem cholinergic system in the execution of orienting behaviors including saccadic eye movements.
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Felix, Richard A., Vicente A. Chavez, Dyana M. Novicio, Barbara J. Morley, and Christine V. Portfors. "Nicotinic acetylcholine receptor subunit α7-knockout mice exhibit degraded auditory temporal processing." Journal of Neurophysiology 122, no. 2 (August 1, 2019): 451–65. http://dx.doi.org/10.1152/jn.00170.2019.
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The CHRNA7 gene that encodes the α7-subunit of the nicotinic acetylcholine receptor (α7-nAChR) has been associated with some autism spectrum disorders and other neurodevelopmental conditions characterized, in part, by auditory and language impairment. These conditions may include auditory processing disorders that represent impaired timing of neural activity, often accompanied by problems understanding speech. Here, we measure timing properties of sound-evoked activity via the auditory brainstem response (ABR) of α7-nAChR knockout mice of both sexes and wild-type colony controls. We find a significant timing delay in evoked ABR signals that represents midbrain activity in knockouts. We also examine spike-timing properties of neurons in the inferior colliculus, a midbrain nucleus that exhibits high levels of α7-nAChR during development. We find delays of evoked responses along with degraded spiking precision in knockout animals. We find similar timing deficits in responses of neurons in the superior paraolivary nucleus and ventral nucleus of the lateral lemniscus, which are brainstem nuclei thought to shape temporal precision in the midbrain. In addition, we find that other measures of temporal acuity including forward masking and gap detection are impaired for knockout animals. We conclude that altered temporal processing at the level of the brainstem in α7-nAChR-deficient mice may contribute to degraded spike timing in the midbrain, which may underlie the observed timing delay in the ABR signals. Our findings are consistent with a role for the α7-nAChR in types of neurodevelopmental and auditory processing disorders and we identify potential neural targets for intervention. NEW & NOTEWORTHY Disrupted signaling via the α7-nicotinic acetylcholine receptor (α7-nAChR) is associated with neurodevelopmental disorders that include impaired auditory processing. The underlying causes of dysfunction are not known but a common feature is abnormal timing of neural activity. We examined temporal processing of α7-nAChR knockout mice and wild-type controls. We found degraded spike timing of neurons in knockout animals, which manifests at the level of the auditory brainstem and midbrain.
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Rakhilin, Sergey, Renaldo C. Drisdel, Daphna Sagher, Daniel S. McGehee, Yolanda Vallejo, and William N. Green. "α-Bungarotoxin Receptors Contain α7 Subunits in Two Different Disulfide-Bonded Conformations." Journal of Cell Biology 146, no. 1 (July 12, 1999): 203–18. http://dx.doi.org/10.1083/jcb.146.1.203.
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Neuronal nicotinic α7 subunits assemble into cell-surface complexes that neither function nor bind α-bungarotoxin when expressed in tsA201 cells. Functional α-bungarotoxin receptors are expressed if the membrane-spanning and cytoplasmic domains of the α7 subunit are replaced by the homologous regions of the serotonin-3 receptor subunit. Bgt-binding surface receptors assembled from chimeric α7/serotonin-3 subunits contain subunits in two different conformations as shown by differences in redox state and other features of the subunits. In contrast, α7 subunit complexes in the same cell line contain subunits in a single conformation. The appearance of a second α7/serotonin-3 subunit conformation coincides with the formation of α-bungarotoxin–binding sites and intrasubunit disulfide bonding, apparently within the α7 domain of the α7/serotonin-3 chimera. In cell lines of neuronal origin that produce functional α7 receptors, α7 subunits undergo a conformational change similar to α7/serotonin-3 subunits. α7 subunits, thus, can fold and assemble by two different pathways. Subunits in a single conformation assemble into nonfunctional receptors, or subunits expressed in specialized cells undergo additional processing to produce functional, α-bungarotoxin–binding receptors with two α7 conformations. Our results suggest that α7 subunit diversity can be achieved postranslationally and is required for functional homomeric receptors.
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STRANG, CHRISTIANNE E., JORDAN M. RENNA, FRANKLIN R. AMTHOR, and KENT T. KEYSER. "Nicotinic acetylcholine receptor expression by directionally selective ganglion cells." Visual Neuroscience 24, no. 4 (July 2007): 523–33. http://dx.doi.org/10.1017/s0952523807070435.
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Acetylcholine (ACh) enhances the preferred direction responses of directionally selective ganglion cells (DS GCs; Ariel & Daw, 1982; Ariel & Adolph, 1985) through the activation of nicotinic acetylcholine receptors (nAChRs; Ariel & Daw, 1982; Massey et al., 1997; Kittila & Massey, 1997). DS GCs appear to express at least two types of nAChRs, those that are sensitive to the partially subtype-specific antagonist methyllycaconitine (MLA), and those that are MLA-insensitive (Reed et al., 2002). Our purpose was to confirm the expression of α7 nAChRs by DS GCs and to assess the contributions of other nAChR subtypes to DS GC responses. Using choline as a nAChR partially subtype-specific agonist, we found that the majority of DS GCs demonstrated responses to choline while under synaptic blockade. The blockade or reduction of choline-induced responses by bath application of nanomolar (nM) concentrations of MLA provided direct evidence that the choline responses were mediated by α7 nAChRs. Because choline is a partial agonist for α3β4 nAChRs (Alkondon et al., 1997), the residual choline responses are consistent with mediation by α3β4 nAChRs. Additionally, a subset of DS GCs responded to nicotine but not to choline, indicating the expression of a third nAChR subtype. The pharmacological results were supported by single cell reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry experiments. The expression of α7 and specific non-α7 nAChR subtypes was correlated with the preferred direction. This indicates the possibility of differential responses to ACh depending on the direction of movement. This is the first description of differential expression of multiple nAChR subtypes by DS GCs.
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Rothbard, Jonathan B., Jesse J. Rothbard, Luis Soares, C. Garrison Fathman, and Lawrence Steinman. "Identification of a common immune regulatory pathway induced by small heat shock proteins, amyloid fibrils, and nicotine." Proceedings of the National Academy of Sciences 115, no. 27 (June 18, 2018): 7081–86. http://dx.doi.org/10.1073/pnas.1804599115.
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Although certain dogma portrays amyloid fibrils as drivers of neurodegenerative disease and neuroinflammation, we have found, paradoxically, that amyloid fibrils and small heat shock proteins (sHsps) are therapeutic in experimental autoimmune encephalomyelitis (EAE). They reduce clinical paralysis and induce immunosuppressive pathways, diminishing inflammation. A key question was the identification of the target for these molecules. When sHsps and amyloid fibrils were chemically cross-linked to immune cells, a limited number of proteins were precipitated, including the α7 nicotinic acetylcholine receptor (α7 NAChR). The α7 NAChR is noteworthy among the over 20 known receptors for amyloid fibrils, because it plays a central role in a well-defined immune-suppressive pathway. Competitive binding between amyloid fibrils and α-bungarotoxin to peritoneal macrophages (MΦs) confirmed the involvement of α7 NAChR. The mechanism of immune suppression was explored, and, similar to nicotine, amyloid fibrils inhibited LPS induction of a common set of inflammatory cytokines while inducing Stat3 signaling and autophagy. Consistent with this, previous studies have established that nicotine, sHsps, and amyloid fibrils all were effective therapeutics in EAE. Interestingly, B lymphocytes were needed for the therapeutic effect. These results suggest that agonists of α7 NAChR might have therapeutic benefit for a variety of inflammatory diseases.
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Baranowska, Urszula, and Róża Julia Wiśniewska. "The α7-nACh nicotinic receptor and its role in memory and selected diseases of the central nervous system." Postępy Higieny i Medycyny Doświadczalnej 71, no. 1 (July 30, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.3844.
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α7-nACh is one of the major nicotinic cholinergic receptor subtypes found in the brain. It is broadly expressed in the hippocampal and cortical neurons, the regions which play a key role in memory formation. Although α7-nACh receptors may serve as postsynaptic receptors mediating classical neurotransmission, they usually function as presynaptic modulators responsible for the release of other neurotransmitters, such as glutamate, γ-aminobutyric acid, dopamine, and norepinephrine. They can, therefore, affect a wide array of neurobiological functions. In recent years, research has found that a large number of agonists and positive allosteric modulators of α7-nAChR induce beneficial effects on learning and memory. Consistently, mice deficient in chrna7 (the gene encoding α7-nAChR protein), are characterized by memory deficits. In addition, decreased expression and function of α7-nAChR is associated agoniwith many neurological diseases including schizophrenia, bipolar disorder, learning disability, attention deficit hyperactivity disorder, Alzheimer disease, autism, and epilepsy. In the recent years many animal experiments and clinical trials using α7-nAChR ligands were conducted. The results of these studies strongly indicate that agonists and positive allosteric modulators of α7-nAChR are promising therapeutic agents for diseases associated with cognitive deficits.
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Strang, Christianne E., Margot E. Andison, Franklin R. Amthor, and Kent T. Keyser. "Rabbit retinal ganglion cells express functional α7 nicotinic acetylcholine receptors." American Journal of Physiology-Cell Physiology 289, no. 3 (September 2005): C644—C655. http://dx.doi.org/10.1152/ajpcell.00633.2004.
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It is well known that cholinergic agents affect ganglion cell (GC) firing rates and light responses in the retinas of many species, but the specific receptor subtypes involved in mediating these effects have been only partially characterized. We sought to determine whether functional α7 nicotinic acetylcholine receptors (nAChRs) contribute to the responses of specific retinal GC classes in rabbit retina. We used electrophysiology, pharmacology, immunohistochemistry, and reverse transcriptase-polymerase chain reaction to determine the pharmacological properties and expression of nAChR subtypes by specific rabbit retinal GC classes. Choline was used as an α7 nAChR agonist. Methyllycaconitine (MLA) was used as a competitive α7 nAChR antagonist. The application of choline before synaptic blockade resulted in changes in retinal GC activity, including increases or decreases in maintained firing and/or enhancement or suppression of light responses. Many physiologically identified GC types, including sustained off, sustained on, transient off, and transient on cells, demonstrated responses to choline application while under synaptic blockade. The choline-induced responses could be blocked with MLA, confirming α7 nAChR activation. Individual choline-responsive GCs displayed mRNA transcripts consistent with the expression of functional α7 nAChRs. Other GCs demonstrated physiological responses and mRNA expression consistent with the expression of both α7 and non-α7 nAChRs. Thus mRNA is present for multiple nAChR subunits in whole retina extracts, and functional α7 nAChRs are capable of modulating the responses of GCs in adult rabbit retina. We also demonstrate through physiological responses that subsets of GCs express more than one nAChR subtype.
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Hilmas, Corey, Edna F. R. Pereira, Manickavasagom Alkondon, Arash Rassoulpour, Robert Schwarcz, and Edson X. Albuquerque. "The Brain Metabolite Kynurenic Acid Inhibits α7 Nicotinic Receptor Activity and Increases Non-α7 Nicotinic Receptor Expression: Physiopathological Implications." Journal of Neuroscience 21, no. 19 (October 1, 2001): 7463–73. http://dx.doi.org/10.1523/jneurosci.21-19-07463.2001.
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Becker, Benjamin, Eva M. Klein, Nadine Striepens, Yoan Mihov, Thomas E. Schlaepfer, Juergen Reul, Liesbet Goossens, Koen Schruers, Keith M. Kendrick, and René Hurlemann. "Nicotinic Acetylcholine Receptors Contribute to Learning-induced Metaplasticity in the Hippocampus." Journal of Cognitive Neuroscience 25, no. 7 (July 2013): 986–97. http://dx.doi.org/10.1162/jocn_a_00383.
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Hippocampal learning is thought to induce metaplasticity, which can facilitate subsequent learning. Administered at single low doses, the N-methyl-d-aspartate-type glutamate receptor antagonist memantine predominantly blocks α7 nicotinic acetylcholine receptors (α7 nAChRs). Placebo-controlled administration of a single low dose of memantine in a pharmaco-fMRI experiment may thus help characterize the role of α7 nAChRs in hippocampal metaplasticity. We hypothesized that if α7 nAChRs contribute to learning-induced metaplasticity in the hippocampus, blockade of these receptors with low-dose memantine would selectively interfere with a facilitation of subsequent learning without impairing hippocampal learning per se. To specifically test this hypothesis, we devised a randomized controlled trial in which healthy volunteers were administered a 20-mg single oral dose of memantine or placebo and scanned on three subsequent runs of a hippocampal learning task. Our results indicate no discrepancies in behavioral learning between low-dose memantine- and placebo-treated participants in the first and second run of this task. In the third run, however, only the placebo-treated group showed facilitated behavioral learning, an effect paralleled by decreased neural responses in the hippocampal cornu ammonis region. Our findings suggest that blockade of α7 nAChRs selectively interfered with a learning-induced facilitation of subsequent learning while leaving unimpaired hippocampal learning per se. Taken together, our results provide support for a relevant contribution of α7 nAChRs to learning-associated metaplasticity in the hippocampus.
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Utkin, Yuri N., Ilia Yu Cherepakhin, Elena V. Kryukova, Irina V. Shelukhina, Yana V. Makarova, Igor E. Kasheverov, Ashis K. Mukherjee, Alexander A. Gusev, and Denis V. Kuznetsov. "Conjugates of α-Cobratoxin with CdSe Quantum Dots: Preparation and Biological Activity." Nano Hybrids and Composites 13 (January 2017): 3–8. http://dx.doi.org/10.4028/www.scientific.net/nhc.13.3.
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α-Cobratoxin is the main neurotoxin in the cobra Naja kaouthia venom; it binds efficiently and selectively with neuronal α7 and muscle type nicotinic acetylcholine receptor and can be used for specific labeling and visualization of these receptors in organs and tissues. For these applications we have prepared conjugates of α-cobratoxin with CdSe quantum dots which have many benefits as compared to organic fluorescent labels. To prepare the conjugate, CdSe quantum dots with ZnS shell were functionalized using a tripeptide glutathione and coupled to toxin using water soluble carbodiimide. The conjugate was purified by gel-filtration chromatography and tested for biological activity. It was found that conjugate preserved the capacity to interact with both neuronal α7 and muscle type nicotinic acetylcholine receptor. Its cytotoxicity to mammalian cells was not higher than that of functionalized quantum dots.
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Cui, Wen-Yan, and Ming D. Li. "Nicotinic Modulation of Innate Immune Pathways Via α7 Nicotinic Acetylcholine Receptor." Journal of Neuroimmune Pharmacology 5, no. 4 (April 13, 2010): 479–88. http://dx.doi.org/10.1007/s11481-010-9210-2.
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Gahring, Lorise C., Elizabeth J. Myers, and Scott W. Rogers. "Inhaled aerosolized nicotine suppresses the lung eosinophilic response to house dust mite allergen." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 4 (October 1, 2020): L683—L692. http://dx.doi.org/10.1152/ajplung.00227.2020.
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Nicotine of unprecedented concentrations and purity is being inhaled by those using commercially available electronic nicotine delivery systems (ENDS). The consequences of this route of self-administration on the immunological response to inhaled allergens are not known. In mice, sensitization and inhalation challenge with the common environmental house dust mite (HDM) allergen is an experimental model of this response. When mice were exposed to aerosolized nicotine base (aeroNic) twice daily, 5 days/wk for 8 wk, the HDM-induced recruitment of eosinophils (EOS) was substantially reduced as measured in bronchial alveolar lavage fluid (BALF). Oral nicotine administration had no effect. HDM challenge in the presence of nicotinic receptor subtype α7 (α7)-specific type-1 positive allosteric modulators (PAMs) was alone sufficient to suppress EOS. RNA analysis of alveolar macrophages (AM) collected from BALF after HDM challenge of aeroNic revealed that α7 activation strongly suppresses initiation of Ccl24 (eotaxin 2) transcription. To examine possible cellular signaling mechanisms coupling α7 to Ccl24 transcription, an AM culture model system was used. In AM cultures of freshly collected BALF, Ccl24 transcription was robustly activated by a mixture of IL-4 and IL-10, and this was suppressed by coapplication of type-1 PAMs through a pathway that requires p38MAPK but is independent of Jak2. These results suggest that the EOS response to HDM inhaled allergen is subject to modulation through activation of the α7 receptor and suggest that the allergic response may be substantially modified in ENDS users.
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Keiger, C. Jane H., Kim R. Jones, L. Douglas Case, Amelia F. Drake, Martin Kendal-Reed, and James C. Walker. "Nicotinic Cholinergic Receptor Expression in the Human Nasal Mucosa." Annals of Otology, Rhinology & Laryngology 112, no. 1 (January 2003): 77–84. http://dx.doi.org/10.1177/000348940311200115.
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Twenty-four nasal mucosa specimens were obtained from the inferior or middle turbinates of 6 normal subjects and 18 patients with chronic sinusitis, inflammatory polyp formation, or sinus allergies. Reverse transcription—polymerase chain reaction analysis was used to identify the non-neuronal nicotinic cholinergic receptor (nAChR) subunits that were expressed in the nasal mucosa. Collectively, transcripts for α (α1, α2, α3, α4, α6, α7) and β (β2, β3, β4) nAChR subunit genes were detected in the respiratory mucosa. The α3, α7, and β2 subunits were expressed in 92%, 88%, and 75% of the subjects, respectively. There was a high degree of interindividual variation in nAChR subunit gene expression among subjects. A significant univariate association was found between tissue type and β4 expression and between gender and β3 expression. These data suggest that cells in the nasal mucosa express the necessary messenger RNAs (mRNAs) for numerous nAChR combinations. Moreover, our identification of nAChR subunit mRNAs in the nasal mucosa extends the findings of other functional studies of nAChRs in nasal epithelial cells and implies that nicotine from tobacco products such as cigarette smoke and nicotine nasal spray may have direct cellular effects on nasal mucosa cells through activation of homogeneous or heterogeneous nAChRs. A significant number of patients receiving nicotine nasal spray have reported nasal irritation, and there are reports of transient irritation of the throat and trachea with the use of smoke-free nicotine cigarettes. These adverse respiratory effects may be due to activation of nAChRs in epithelial cells of the nose and trachea.