共查询到20条相似文献,搜索用时 8 毫秒
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Yoan Brissonnet Romulo Araoz Rui Sousa Lucie Percevault Sami Brument David Deniaud Denis Servent Jean-Yves Le Questel Jacques Lebreton Sébastien G. Gouin 《Bioorganic & medicinal chemistry》2019,27(5):700-707
In the field of nicotinic acetylcholine receptors (nAChRs), recognized as important therapeutic targets, much effort has been dedicated to the development of nicotinic analogues to agonize or antagonize distinct homo- and heteropentamers nAChR subtypes, selectively. In this work we developed di- and heptavalent nicotinic derivatives based on ethylene glycol (EG) and cyclodextrin cores, respectively. The compounds showed a concentration dependent inhibition of acetylcholine-induced currents on α7 nAChR expressed by Xenopus oocytes. Interesting features were observed with the divalent nicotinic derivatives, acting as antagonists with varied inhibitory concentrations (IC50) in function of the spacer arm length. The best divalent compounds showed a 16-fold lowered IC50 compared to the monovalent reference (12 vs 195?µM). Docking investigations provide guidelines to rationalize these experimental findings. 相似文献
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α7 nicotinic acetylcholine receptors (α7nAChRs) have been targeted to improve cognition in different neurological and psychiatric disorders. Nevertheless, no α7nAChR activating ligand has been clinically approved. Here, we investigated the effects of antagonizing α7nAChRs using the selective antagonist methyllycaconitine (MLA) on receptor activity in vitro and cognitive functioning in vivo. Picomolar concentrations of MLA significantly potentiated receptor responses in electrophysiological experiments mimicking the in vivo situation. Furthermore, microdialysis studies showed that MLA administration substantially increased hippocampal glutamate efflux which is related to memory processes. Accordingly, pre-tetanus administration of low MLA concentrations produced longer lasting potentiation (long-term potentiation, LTP) in studies examining hippocampal plasticity. Moreover, low doses of MLA improved acquisition, but not consolidation memory processes in rats. While the focus to enhance cognition by modulating α7nAChRs lies on agonists and positive modulators, antagonists at low doses should provide a novel approach to improve cognition in neurological and psychiatric disorders. 相似文献
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Ya. V. Makarova I. V. Shelukhina A. K. Mukherjee D. V. Kuznetsov V. I. Tsetlin Yu. N. Utkin 《Doklady. Biochemistry and biophysics》2017,475(1):253-255
Fluorescent derivatives are widely used to study the structure and functions of proteins. Quantum dots (QDs), fluorescent semiconductor nanocrystals, have a high quantum yield and are much more resistant to bleaching compared to organic dyes. Conjugates of α-neurotoxins with QDs were used for visualization of human α7 acetylcholine receptors heterologously expressed in GH4C1 pituitary adenoma cells. Specific staining of cells by the conjugated toxins was observed. 相似文献
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In vitro studies suggest that α7 nicotinic receptors located on striatal glutamatergic terminals stimulate the release of glutamate which in turn acts at ionotropic glutamate receptors on dopaminergic terminals to increase dopamine release. However, this mechanism has never been observed in in vivo studies. In the present work, the effect of the nicotinic receptors agonist, anatoxin-a, on striatal glutamate and dopamine release has been studied. Using in vivo microdialysis technique, our results have shown that anatoxin-a evokes glutamate release in a dependent way of activation α7 nicotinic receptors. The increase of glutamate is followed by an increase on dopamine levels. These results represent a clear in vivo evidence of the striatal modulation of dopamine by means of glutamate release through α7 nicotinic receptors. 相似文献
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Uteshev VV 《PloS one》2012,7(3):e32951
Positive allosteric modulators of highly Ca(2+)-permeable α7 nicotinic acetylcholine receptors, such as PNU-120596, may become useful therapeutic tools supporting neuronal survival and function. However, despite promising results, the initial optimism has been tempered by the concerns for cytotoxicity. The same concentration of a given nicotinic agent can be neuroprotective, ineffective or neurotoxic due to differences in the expression of α7 receptors and susceptibility to Ca(2+) influx among various subtypes of neurons. Resolution of these concerns may require an ability to reliably detect, evaluate and optimize the extent of α7 somatic ionic influx, a key determinant of the likelihood of neuronal survival and function. In the presence of PNU-120596 and physiological choline (~10 μM), the activity of individual α7 channels can be detected in whole-cell recordings as step-like current/voltage deviations. However, the extent of α7 somatic influx remains elusive because the activity of individual α7 channels may not be integrated across the entire soma, instead affecting only specific subdomains located in the channel vicinity. Such a compartmentalization may obstruct detection and integration of α7 currents, causing an underestimation of α7 activity. By contrast, if step-like α7 currents are integrated across the soma, then a reliable quantification of α7 influx in whole-cell recordings is possible and could provide a rational basis for optimization of conditions that support survival of α7-expressing neurons. This approach can be used to directly correlate α7 single-channel activity to neuronal function. In this study, somatic dual-patch recordings were conducted using large hypothalamic and hippocampal neurons in acute coronal rat brain slices. The results demonstrate that the membrane electrotonic properties do not impede somatic signaling, allowing reliable estimates of somatic ionic and Ca(2+) influx through α7 channels, while the somatic space-clamp error is minimal (~0.01 mV/μm). These research efforts could benefit optimization of potential α7-PAM-based therapies. 相似文献
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α7 nicotinic receptors are highly permeable to Ca2+ as well as monovalent cations. We extended the characterization of the Ca2+ permeation of non-desensitizing chick α7 receptors (S240T/L247T α7 nAChRs) expressed in Xenopus oocytes by (1) measuring the concentration dependence of conductance under conditions in which Ca2+ or Ba2+ were the only permeant cations in the extracellular solution, and (2) measuring the concentration dependence of Ca2+ block of K+ currents through the receptors. The first set of experiments yielded an apparent affinity of 0.96 mM Ca2+ activity (2.4 mM concentration) for Ca2+ permeation and an apparent affinity of 0.65 mM Ba2+ activity (1.7 mM concentration) for Ba2+ permeation. The apparent affinity of Ca2+ inhibition of K+ currents was 0.49 mM activity (1.5 mM concentration). The similarity of these apparent affinities in the millimolar range suggests that the pore of α7 receptors has one or more low-affinity Ca2+ binding sites and no high-affinity sites. 相似文献
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Dorothée Gilbert Marzia Lecchi Serge Arnaudeau Daniel Bertrand Nicolas Demaurex 《Cell calcium》2009,45(2):198-207
Neuronal nicotinic acetylcholine receptors (nAChRs) are Ca2+-permeable ligand-gated channels widely expressed in the central and peripheral nervous system. One of the most Ca2+ selective isoform is the homopentameric α7-nAChR implicated in schizophrenia. The activity of α7-nAChRs is usually recorded electrophysiologically, which limits the amount of information obtained. Here, we used fluorescence imaging to record Ca2+ transients associated with activation of the α7-nAChR in neuroblastoma cells stably expressing human α7-nAChRs. Application of nicotine (50 μM) consistently evoked transient (30 s), stereotyped Ca2+ responses that were inhibited by the selective α7-nAChRs antagonists methyllycaconitine (MLA) and α-bungarotoxin, and greatly increased and prolonged by the allosteric modulator PNU-120596 (1 μM). Unexpectedly, brief (1–5 s), repetitive Ca2+ transients of sub-micrometric dimension were observed in filopodia of cells expressing α7-nAChR. PNU-120596 increased the frequency and slowed the decay kinetics of these miniature Ca2+ elevations, which were insensitive to ryanodine, preserved during hyperpolarisation, and prevented by MLA, α-bungarotoxin, or Ca2+ removal. Global Ca2+ responses were also recorded in ganglion cells of embryo chicken retina during co-application of PNU-120596 and nicotine, together with whole-cell currents and brief current bursts. These data demonstrate that Ca2+ signals generated by α7-nAChRs can be recorded optically both in cell lines and in intact tissues. The possibility to image miniature Ca2+ signals enables to map the location of functional α7-nAChR channel clusters within cells and to analyze their single channel properties optically. Deciphering the rich pattern of intracellular Ca2+ signals generated by the activity of the α7-nAChRs will reveal the physiological role of these receptor-channels. 相似文献
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Meza RC Ortiz FC Bravo E Iturriaga-Vásquez P Eugenín JL Varas R 《Neurochemistry international》2012,60(2):115-124
The carotid bodies (CBs) are chemosensory organs that respond to hypoxemia with transmitter neurosecretion, leading to a respiratory reflex response. It has been proposed that acetylcholine is a key regulator of transmitter release through activation of presynaptic nicotinic acetylcholine receptors (nAChRs). In the present work, we studied the identity of such nAChRs and their contribution to catecholamine release from CBs. Neonatal rat CBs were placed in a recording chamber for electrochemical recordings or disassociated for voltage-clamp studies on isolated cells. Fast nicotine superfusion increases catecholamine release from intact CBs. This response was diminished reversibly by the non-selective nAChR blocker hexamethonium, by the selective α7 blocker α-bungarotoxin and by the α4-containing nAChR blocker erysodine. In isolated CB cells the nAChR agonists nicotine, acetylcholine and cytisine all evoke inward currents with similar potencies. The nicotine-evoked current was fully blocked by mecamylamine and partially inhibited by α-bungarotoxin or erysodine. However, the combination of both α-bungarotoxin an erysodine failed to suppress this response. Immunodetection studies confirm the presence of α7 and α4 subunits in isolated dopaminergic CB cells. Our results show that activation of α7 and/or α4-containing nAChR subtypes have the ability to regulate catecholamine release from intact CB due to activation of fast inward currents expressed in chemoreceptor cells. Therefore, our results suggest that both nAChR subtypes contribute to the cholinergic nicotinic regulation of catecholamine signaling in the carotid body system. 相似文献
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Long‐term treatment with nicotine or selective α7 nicotinic acetylcholine receptor (nAChR) agonists increases the number of α7 nAChRs and this up‐regulation may be involved in the mechanism underlying the sustained procognitive effect of these compounds. Here, we investigate the influence of type I and II α7 nAChR positive allosteric modulators (PAMs) on agonist‐induced α7 nAChR up‐regulation. We show that the type II PAMs, PNU‐120596 (10 μM) or TQS (1 and 10 μM), inhibit up‐regulation, as measured by protein levels, induced by the α7 nAChR agonist A‐582941 (10 nM or 10 μM), in SH‐EP1 cells stably expressing human α7 nAChR, whereas the type I PAMs AVL‐3288 or NS1738 do not. Contrarily, neither type I nor II PAMs affect 10 μM nicotine‐induced receptor up‐regulation, suggesting that nicotine and A‐582941 induce up‐regulation through different mechanisms. We further show in vivo that 3 mg/kg PNU‐120596 inhibits up‐regulation of the α7 nAChR induced by 10 mg/kg A‐582941, as measured by [125I]‐bungarotoxin autoradiography, whereas 1 mg/kg AVL‐3288 does not. Given that type II PAMs decrease desensitization of the receptor, whereas type I PAMs do not, these results suggest that receptor desensitization is involved in A‐582941‐induced up‐regulation. Our results are the first to show an in vivo difference between type I and II α7 nAChR PAMs, and demonstrate an agonist‐dependent effect of type II PAMs occurring on a much longer time scale than previously appreciated. Furthermore, our data suggest that nicotine and A‐582941 induce up‐regulation through different mechanisms, and that this confers differential sensitivity to the effects of α7 nAChR PAMs. These results may have implications for the clinical development of α7 nAChR PAMs. 相似文献
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Xiao-Jing Wang Ying-Feng Liu Qing-Yu Wang Morito Tsuruoka Kazumasa Ohta Sheng-Xi Wu Masashi Yakushiji Takashi Inoue 《Cell and tissue research》2010,340(2):347-355
Tobacco smoking is the main risk factor associated with chronic periodontitis, but the mechanisms that underlie this relationship
are largely unknown. Recent reports proposed that nicotine plays an important role in tobacco-related morbidity by acting
through the nicotinic acetylcholine receptors (nAChRs) expressed by non-neuronal cells. The aim of this study was to investigate
whether α7 nAChR was expressed in periodontal tissues and whether it functions by regulating IL-1β in the process of periodontitis.
In vitro, human periodontal ligament (PDL) cells were cultured with 10−12 M of nicotine and/or 10−9 M of alpha-bungarotoxin (α-Btx), a α7 nAChR antagonist. The expression of α7 nAChR and IL-1β in PDL cells and the effects
of nicotine/α-Btx administration on their expression were explored. In vivo, an experimental periodontitis rat model was established,
and the effects of nicotine/α-Btx administration on expression of α7 nAChR and development of periodontitis were evaluated.
We found that α7 nAChR was present in human PDL cells and rat periodontal tissues. The expressions of α7 nAChR and IL-1β were
significantly increased by nicotine administration, whereas α-Btx treatment partially suppressed these effects. This study
was the first to demonstrate the functional expression of α7 nAChR in human PDL cells and rat periodontal tissues. Our results
may be pertinent to a better understanding of the relationships among smoking, nicotine, and periodontitis. 相似文献
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Partial activation of α7 nicotinic acetylcholine receptors: insights from molecular dynamics simulations 总被引:1,自引:0,他引:1
Nicotinic acetylcholine receptors (nAChRs) are drug targets for neuronal disorders and diseases. Partial agonists for nAChRs are currently being developed as drugs for the treatment of neurological diseases for their relative safety originated from reduced excessive stimulation. In the current study, molecular docking, molecular dynamics simulations and binding energy calculations were performed to theoretically investigate the interactions between the partial agonists, 4-OH-DMXBA and tropisetron with α7-nAChR. The results suggest that the partial agonists 4-OH-DMXBA and tropisetron bind with α7-nAChR in a binding mode similar to that with AChBP. The non-conserved residues in the binding sites contribute to the orientation deviation of these partial agonists from their orientation in AChBP. Energy calculation and decomposition using MM-GB/SA suggests that the van der Waals term (ΔEVDW) is the main driving force for the binding of the partial agonists to α7-nAChR. The molecular dynamics simulations showed that the opening of the C-loop binding with the partial agonists is in-between the openings for the binding with the full agonist and in the apo state. This conformation difference for the C-loop sheds light on the partial agonism of nAChR. 相似文献
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Youyi Peng Qiang Zhang Gretchen L. Snyder Hongwen Zhu Wei Yao John Tomesch Roger L. Papke James P. O’Callaghan William J. Welsh Lawrence P. Wennogle 《Bioorganic & medicinal chemistry letters》2010,20(16):4825-4830
Two distinct families of small molecules were discovered as novel α7 nicotinic acetylcholine receptor (nAChR) antagonists by pharmacophore-based virtual screening. These novel antagonists exhibited selectivity for the neuronal α7 subtype over other nAChRs and good brain penetration. Neuroprotection was demonstrated by representative compounds 7i and 8 in a mouse seizure-like behavior model induced by the nerve agent diisopropylfluorophosphate (DFP). These novel nAChR antagonists have potential use as antidote for organophosphorus nerve agent intoxication. 相似文献
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Koval L Lykhmus O Zhmak M Khruschov A Tsetlin V Magrini E Viola A Chernyavsky A Qian J Grando S Komisarenko S Skok M 《The international journal of biochemistry & cell biology》2011,43(4):516-524
Mouse B lymphocytes express several nicotinic acetylcholine receptor (nAChR) subtypes, their exact functions being not clearly understood. Here we show that α7 nAChR was present in about 60%, while α4β2 and α9(α10) nAChRs in about 10% and 20% of mouse spleen B lymphocytes, respectively; Balb/c and C57Bl/6 mice possessed different relative amounts of these nAChR subtypes. α4β2 and α7, but not α9(α10) nAChRs, were up-regulated upon B lymphocyte activation in vitro. Flow cytometry and sandwich ELISA studies demonstrated that α7 and α9(α10) nAChRs are coupled to CD40, whereas α4β2 nAChR is coupled to IgM. B lymphocytes of both α7(-/-) and β2(-/-) mice responded to anti-CD40 stronger than those of the wild-type mice, whereas the cells of β2(-/-) mice responded to anti-IgM worse than those of the wild-type or α7(-/-) mice. Inhibition of α7 and α9(α10) nAChRs with methyllicaconitine resulted in considerable augmentation of CD40-mediated B lymphocyte proliferation in cells of all genotypes; stimulation of α4β2 nAChRs with epibatidine increased the IgM-mediated proliferation of the wild-type and α7(-/-), but not β2(-/-) cells. Inhibition of α9(α10) nAChRs with α-conotoxin PeAI exerted weak stimulating effect on CD40-mediated proliferation. This nAChR subtype was up-regulated in α7(-/-) B-cells. α7 nAChRs were found recruited to immune synapses between human T and B lymphocytes, both of which produced acetylcholine. It is concluded that α7 nAChR fulfills inhibitory CD40-related mitogenic function, α4β2 nAChR produces a stimulatory IgM-related effect, while α9α10 nAChR is a "reserve" receptor, which partly compensates the absence of α7 nAChR in α7(-/-) cells. Acetylcholine is an additional mediator to modulate activation of interacting T and B lymphocytes. 相似文献
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Mura E Zappettini S Preda S Biundo F Lanni C Grilli M Cavallero A Olivero G Salamone A Govoni S Marchi M 《PloS one》2012,7(1):e29661
Background
We previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer''s Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer''s Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA.Methodology/Findings
We used a dual approach: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA.Conclusions/Significance
The results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used. 相似文献17.
Dallanoce C Matera C De Amici M Rizzi L Pucci L Gotti C Clementi F De Micheli C 《Chirality》2012,24(7):543-551
Epiboxidine hydrochlorides (+)-2 and (-)-2, which are the structural analogs of the antipodes of epibatidine (±)-1, as well as the enantiomeric pairs (+)-3/(-)-3 and (+)-4/(-)-4 were synthesized and tested for binding affinity at α4β2 and α7 nicotinic acetylcholine receptor (nAChR) subtypes. Final derivatives were prepared through the condensation of racemic N-Boc-7-azabicyclo[2.2.1]heptane-2-one (±)-5 with the resolving agent (R)-(+)-2-methyl-2-propanesulfinamide. The pharmacological analysis carried out on the three new enantiomeric pairs evidenced an overall negligible degree of enantioselectivity at both nAChRs subtypes, a result similar to that reported for both natural and unnatural epibatidine enantiomers at the same investigated receptor subtypes. 相似文献
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Antibodies against peripheral nicotinic acetylcholine receptors (nAChR) were used to determine the proportion of brain α-bungarotoxin binding sites that are immunologically related to the peripheral nAChR. The α-bungarotoxin binding component partially purified from rat brain was labelled with [125I]α-bungarotoxin and reacted with increasing concentrations of rabbit anti(nAChR) antisera. At least 75% of the brain protein could be immunoprecipitated by rabbit anti(rat muscle junctional nAChR) antiserum (M) whereas an antiserum against Torpedo nAChR (J) was without effect and clearly failed to cross-react with the brain component. Both antisera precipitated 100% of [125I]α-bungarotoxin-labelled nAChR from Torpedo marmorata. The lower precipitation of the brain protein was not a consequence of [125I]α-bungarotoxin dissociating during the precipitation. We conclude that the majority of α-bungarotoxin binding sites in brain are clearly recognised by the crossreacting antiserum.Release of [3H]dopamine from striatal synaptosomes could be elicited by nicotine in a dose-dependent manner and the response was prevented by the ganglionic blocker mecamylamine, although antagonism by α-bungarotoxin was less clearcut. Preincubation of the synaptosomes with antiserum M resulted in a statistically significant decrease in the [3H]dopamine response to nicotine at all agonist concentrations tested. Antiserum J, however, had no consistent effect on the response. Thus the actions of the antisera parallel their ability to recognise the brain α-bungarotoxin binding component. We conclude that the cholinergic regulation of dopamine release is in part mediated through a nAChR that is immunologically related to the nAChR of the neuromuscular junction and to the α-bungarotoxin binding component that can be isolated from rat brain. 相似文献
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Zakhar O. Shenkarev Mikhail A. Shulepko Maxim L. Bychkov Dmitrii S. Kulbatskii Olga V. Shlepova Nathalia A. Vasilyeva Alexander A. Andreev-Andrievskiy Anfisa S. Popova Evgeniya A. Lagereva Eugene V. Loktyushov Sergey G. Koshelev Morten S. Thomsen Dmitry A. Dolgikh Sergey A. Kozlov Pavel M. Balaban Mikhail P. Kirpichnikov Ekaterina N. Lyukmanova 《Journal of neurochemistry》2020,155(1):45-61
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