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Breast cancer:Muscarinic receptors as new targets for tumor therapy
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作者 Alejandro Español Agustina Salem +1 位作者 Yamila Sanchez María Elena Sales 《World Journal of Clinical Oncology》 CAS 2021年第6期404-428,共25页
The development of breast cancer is a complex process that involves the participation of different factors.Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors(mAChRs)in different... The development of breast cancer is a complex process that involves the participation of different factors.Several authors have demonstrated the overexpression of muscarinic acetylcholine receptors(mAChRs)in different tumor tissues and their role in the modulation of tumor biology,positioning them as therapeutic targets in cancer.The conventional treatment for breast cancer involves surgery,radiotherapy,and/or chemotherapy.The latter presents disadvantages such as limited specificity,the appearance of resistance to treatment and other side effects.To prevent these side effects,several schedules of drug administration,like metronomic therapy,have been developed.Metronomic therapy is a type of chemotherapy in which one or more drugs are administered at low concentrations repetitively.Recently,two chemotherapeutic agents usually used to treat breast cancer have been considered able to activate mAChRs.The combination of low concentrations of these chemotherapeutic agents with muscarinic agonists could be a useful option to be applied in breast cancer treatment,since this combination not only reduces tumor cell survival without affecting normal cells,but also decreases pathological neo-angiogenesis,the expression of drug extrusion proteins and the cancer stem cell fraction.In this review,we focus on the previous evidences that have positioned mAChRs as relevant therapeutic targets in breast cancer and analyze the effects of administering muscarinic agonists in combination with conventional chemotherapeutic agents in a metronomic schedule. 展开更多
关键词 muscarinic receptors Drug therapy Breast cancer Drug combination Metronomic therapy Drug resistance
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Effect of Daicong solution on hippocampal muscarinic receptors 1 and 3 gene expression in a rat model of Alzheimer’s disease
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作者 Hongyan Wang Shumei Zhao +4 位作者 Qi'an Yue Lefa Yan Ying Gong Rui Ji Jingzong Gao 《Neural Regeneration Research》 SCIE CAS CSCD 2008年第7期719-722,共4页
BACKGROUND: It has been previously shown that the muscarinic (M) receptor is involved in brain arousal and selective attention, mood, and motor coordination. OBJECTIVE: To explore the effects of various intragastr... BACKGROUND: It has been previously shown that the muscarinic (M) receptor is involved in brain arousal and selective attention, mood, and motor coordination. OBJECTIVE: To explore the effects of various intragastric Daicong doses on hippocampal MI and M3 receptor gene expression in a rat model of Alzheimer's disease. DESIGN, TIME AND SETTING: A randomized cellular and molecular biology experiment, conducted at the Molecular Immunology Laboratory in Shandong between October 2006 and April 2007. MATERIALS: Fifty 22-month old Sprague Dawley rats, weighing 250-300 g were used for this experiment. Kainic acid was used to lesion the nucleus basalis to establish a rat model of Alzheimer's disease. The components of Daicong solution were as follows: ginseng, rehmannia dride rhizome, anemarrhena, and radix astragali. The solution was provided by the Affiliated Hospital to Weifang Medical College, according to preparation techniques of extracting liquid for traditional Chinese medicine (1 g crude drug/mL solution). Kainic acid was provided by Professor Xiuyan Li at Weifang Medical College. METHODS: The rats were randomly divided into 5 groups, 10 rats in each group. Four groups were used for model establishment, and the fifth group served as a normal control group. Three of the model groups were intragastrically administered 5, 10, and 20 g/kg/d Daicong solution, and an additional model group and normal control group received normal saline (10 mL/kg/d). Drugs were administered over a time period of one month. MAIN OUTCOME MEASURES: Four days after model establishment, Morris water maze was used to measure learning and memory capabilities. RT-PCR was used to detect the effect of Daicong solution on mRNA expression of M1 and M3 receptor in the hippocampus of all groups. RESULTS: Fifty rats were included in the final analysis, without any loss. M1 and M3 receptor mRNA expression was decreased in the model group, compared to the normal control group (P 〈 0.05). Upon Daicong administration (10 g/kg/d and 20 g/kg/d), M1 and M3 receptor mRNA expression significantly increased in the hippocampus, compared to the model group (P 〈 0.05). M1 and M3 mRNA expression was greatest in the 10 g/kg/d group. CONCLUSION: A 10 g/kg/d solution of Daicong can improve M1 and M3 receptor mRNA expression in the hippocampus of a rat model of Alzheimer's disease. 展开更多
关键词 Alzheimer's disease RATS muscarinic receptor traditional Chinese medicine
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M_(4) muscarinic receptors regulates dopamine/DARPP-32 signaling and glutamate transmis⁃sion to balance dopaminergic D1 function in mouse dorsal striatum
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作者 ZHOU Hu ZHANG Jing-xin +5 位作者 LI Xing SHI Hua-xiang SUI Xin WANG Yong-an LI Jin WANG Li-yun 《中国药理学与毒理学杂志》 CAS 北大核心 2021年第9期689-689,共1页
OBJECTIVE Abnormal striatal dopaminergic and glutamatergic neurotransmis⁃sion is central to the pathophysiology of schizo⁃phrenia.In this study,we investigated the roles of M4 receptor interplay with D1 signaling in s... OBJECTIVE Abnormal striatal dopaminergic and glutamatergic neurotransmis⁃sion is central to the pathophysiology of schizo⁃phrenia.In this study,we investigated the roles of M4 receptor interplay with D1 signaling in stria⁃tal neurotransmission that affect glutamatergic transmission to control the etiology of neuropsy⁃chiatric disorders.METHODS To study dorsal striatum(DS)region-specific neuronal and behav⁃ioral responses modulated by M4 receptors,we used clustered regularly interspaced short palin⁃dromic repeats-associated protein 9 technology to generate mice lacking M4 in the dorsal stria⁃tum(DS-M4-KD).The M4 positive allosteric modu⁃lator,VU0467154,were used to study the phar⁃macologically profiles with M4 receptor stimula⁃tion in WT mice.Oxotremorine M(Oxo-M),a no subtype-selective muscarinic agonist,was used to show that mAchRs activation,in order to dissect the particular function of M4,in DS-M4-KD mice.Open filed test and forced swim test were used to assess the change of psychiatric-like behav⁃iors.Western blotting and immunohistochemistry were used to detect protein levels of phosphory⁃lation site of dopamine-and cAMP-regulated phosphoprotein of 32 ku(DARPP-32).Whole-cell patch-clamp recording was used to assess M4-mediated cholinergic inhibition of glutamater⁃gic synaptic input transmission.RESULTS West⁃ern blotting and immunohistochemistry assay showed VU0467154(5 mg·kg-1,ip)promoted phosphorylation of DARPP-32 at Thr75,and atten⁃uated D1-dependent phosphorylation of DARPP-32 at Thr34 within the mouse DS.Consistently,the Oxo-M(4μg,icv)also increased DARPP-32 phosphorylation at site Thr75 to reversed phos⁃phorylation at site Thr34 in WT mice,but not in DS-M4-KD mice.In parallel with altered DARPP-32 responses,VU0467154 or Oxo-M evoked a psychological stress response and reversed D1-induced hyperlocomotion in mice in open field test and force swim tests.However,Oxo-M sup⁃pression of D1-depengdeng behavioral respons⁃es was impaired in DS-M4-KD mice.Whole-cell patch recording showed that VU0467154 or Oxo-M mediated endogenous cholinergic inhibition of miniature excitatory postsynaptic currents through M4 receptors,which in turn suppressed D1-depen⁃dent glutamatergic synaptic transmission in the DS.CONCLUSION This study provides evidence for the role of M4 receptors in regulation of dopa⁃mine/DARPP-32 signaling and glutamate respons⁃es in the DS,and therefore modulation of psychi⁃atric behaviors associated with D1 signaling.This results indicate the mechanisms of treatments targeting M4 in psychiatric disorders. 展开更多
关键词 dorsal striatum dopamine receptor 1 muscarinic acetylcholine M4 receptor dopamine-and cAMP-regulated phosphoprotein of 32 ku
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Characterization of subtype selection properties of R-(-)-DM-phencynonate hydrochloride and its racemate on muscarinic receptors
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作者 王丽韫 孙洪良 +3 位作者 牟男 仲伯华 刘克良 郑建全 《Journal of Chinese Pharmaceutical Sciences》 CAS 2009年第2期121-127,共7页
In order to compare the potential selectivity of R-(-)-DM-phencynonate hydrochloride with its racemate (±)-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylch... In order to compare the potential selectivity of R-(-)-DM-phencynonate hydrochloride with its racemate (±)-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylcholine muscarinic receptor subtypes (M1- M5) (CHO-hml-5R) were cloned and expressed in Chinese hamster ovary (CHO-K1) cell line. The specific mRNAs of the five acetylcholine muscarinic receptor subtypes were detected by the reverse transcription-polymerase chain reaction (RT-PCR) method, demonstrating the definite expression of muscarinic receptor subtype genes (CHO-hml-5R). The affinity and saturability of different muscarinic receptor subtypes to [^3H] N-methylscopolamine ([^3H]-NMS) were obtained by radioligand binding assay. Equilibrium binding assay revealed that the maximum binding capacity of [^3H]-NMS (Bmax value) to CHO-hml-5R were 40.22±3.23, 24.53±4.11, 29.65±2.65, 25.41±2.46, 32.78±4.81 pmol/mg·protein, respectively. Kd values of [^3H]-NMS to muscarinic receptors M1 to M5 were 0.97±0.22, 1.16±0.14, 0.99±0.06, 0.56±0.08, 1.12±0.06 nM, respectively. R-(-)-DM- phencynonate hydrochloride was found to block the M4 receptor with a much higher potency (pD2 = 7.48) than those displayed on M1 (pD2 = 6.20), M2 (pD2 = 5.99), M3 (pD2 = 5.99) and M5 (pD2 = 6.70) subtypes. However, for (±)-DM-phencynonate hydrochloride, no significant subtype receptor selectivity was found. Both (±)-DM- and R-(-)-DM-phencynonate hydrochloride showed allosteric effects on muscarinic receptors, the Hill coefficient (nH) of five receptor subtypes was less than 1, respectively. The results revealed that R-(-)-DM-phencynonate hydrochloride showed selectivity torwards M4 subtype, and there were allosteric effects for both R-(-)-DM-phencynonate hydrochloride and (±)-DM-phencynonate hydrochloride on muscarinic receptors. 展开更多
关键词 Optical isomers muscarinic acetylcholine receptors (mAChRs) Subtype receptor selectivity Radioligand binding assay
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Effect of ipratropium bromide on airway and pulmonary muscarinic receptors in a rat model of chronic obstructive pulmonary disease 被引量:9
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作者 姚婉贞 王国扬 +2 位作者 朱红 孙永昌 赵鸣武 《Chinese Medical Journal》 SCIE CAS CSCD 2001年第1期80-83,共4页
OBJECTIVE: To observe the level of muscarinic receptors in airway and lung tissues, and the effect of inhaled ipratropium bromide on these receptors in a rat model of chronic obstructive pulmonary disease (COPD). METH... OBJECTIVE: To observe the level of muscarinic receptors in airway and lung tissues, and the effect of inhaled ipratropium bromide on these receptors in a rat model of chronic obstructive pulmonary disease (COPD). METHODS: This model was developed by exposure of rats to 250 ppm SO2 gas, 5 h/d, 5 d/wk, for a period of 7 wk. The COPD rats inhaled 0.025% aerosolized iratropium bromide for 20 min, 2 times daily, in an airtight chamber. Muscarinic receptors in airway and lung tissues of normal rats, ipratropium bromide-treated COPD rats and the recovering COPD rats were measured by the radio-ligand binding assay. RESULTS: Airway/lung pathology and pulmonary function tests showed that chronic SO2 exposure caused pathophysiologic changes similar to those observed in human COPD. The density (0.038 +/- 0.011, pmol/mg protein) and affinity (Kd, 23 +/- 11 pmol/L) of muscarinic receptors in airway and lung tissues of COPD rats were not changed compared with those of normal control rats (0.030 +/- 0.008 and 29 +/- 19, respectively, P > 0.05). Densities of the muscarinic receptors were not changed after inhalation of ipratropium bromide for 5 days, but increased significantly after inhalation for 30 days, as compared with those of the untreated COPD rats. The muscarinic receptors returned the normal levels at day 6 after cessation of ipratropium bromide treatment. There were no differences among different groups of rats in equilibrium dissociation constants (Kd). CONCLUSION: A rat model of COPD with pathophysiologic changes similar to the human counterpart was developed using chronic SO2 exposure. There was no significant change in the number and function of muscarinic receptors in airway and lung tissues of the COPD rats, but upregulation of the muscarinic receptors was observed after long-term inhalation of ipratropium bromide. 展开更多
关键词 Animals Bronchodilator Agents Disease Models Animal Ipratropium Lung Male muscarinic Antagonists Pulmonary Disease Chronic Obstructive RATS Rats Wistar receptors muscarinic Sulfur Dioxide TRACHEA
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Stimulatory activity of anti-peptide antibodies against the second extracellular loop of human M_2 muscarinic receptors 被引量:3
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作者 王文泽 郭光伟 +2 位作者 唐进 李家成 赵荣瑞 《Chinese Medical Journal》 SCIE CAS CSCD 2000年第10期3-7,12,共6页
Obejctive To study the activity of anti peptide antibodies against the second extracellular loop of human M 2 muscarinic receptors on cAMP production and inward calcium currents (I Ca ) in guinea pig ventricula... Obejctive To study the activity of anti peptide antibodies against the second extracellular loop of human M 2 muscarinic receptors on cAMP production and inward calcium currents (I Ca ) in guinea pig ventricular myocytes A comparison was also made with those of a muscarinic receptor agonist Methods cAMP content was determined by radioimmunoassay and the I Ca in guinea pig single ventricular cells were recorded by the whole cell patch clamp technique Results Both the muscarinic receptor agonist, carbachol (Carb 10?μmol/L), and anti peptide antibodies (Abs 100?nmol/L) could decrease basal cAMP levels (by 46 9%±4 2% and 60 2%±4 6%, respectively) and basal I Ca Both Carb (10?μmol/L) and Abs (100?nmol/L) could also inhibit the isoprenaline induced (Iso 0 8?μmol/L) increases in cAMP production (from 108 2±7 0 to 88 4±7 2? pmol/mg·protein/min for Carb and 88 6±5 1? pmol/mg· protein/min for Abs, respectively) and the increases in I Ca The muscarinic receptor antagonist atropine (Atr) was able to prevent these effects of Carb and Abs Conclusions Anti peptide antibodies against an epitope located in the second extracellular loop of human M 2 muscarinic receptors, similar to muscarinic receptor agonist, could decrease the basal I Ca and β receptor agonist stimulated increase of I Ca by decreasing the basal and β receptor agonist stimulated increase of cAMP production, and therefore could have an effect on their target receptor These results further suggest that autoimmunity may participate in the pathogenesis of human cardiomyopathy and the second extracellular loop of human M 2 muscarinic receptor could be the main immunodominant region. 展开更多
关键词 anti-peptide antibodies M_2 muscarinic receptor CAMP calcium currents patch clamp
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Effects of gamma-aminobutyric acid receptors on muscarinic receptor-mediated free calcium ion levels in the facial nucleus following facial nerve injury
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作者 Guangfeng Jiang Dawei Sun +4 位作者 Rui Zhou Fugao Zhu Yanqing Wang Xiuming Wan Banghua Liu 《Neural Regeneration Research》 SCIE CAS CSCD 2011年第11期855-859,共5页
Muscarinic receptors and nicotine receptors can increase free calcium ion levels in the facial nucleus via different channels following facial nerve injury. In addition, γ-aminobutyric acid A (GABAA) receptors have... Muscarinic receptors and nicotine receptors can increase free calcium ion levels in the facial nucleus via different channels following facial nerve injury. In addition, γ-aminobutyric acid A (GABAA) receptors have been shown to negatively regulate free calcium ion levels in the facial nucleus by inhibiting nicotine receptors. The present study investigated the influence of GABAA, γ-aminobutyric acid B (GABAB) and C (GABAc) receptors on muscarinic receptors in rats with facial nerve injury by confocal laser microscopy. GABAA and GABAB receptors exhibited significant dose-dependent inhibitory effects on increased muscarinic receptor-mediated free calcium ion levels following facial nerve injury. Results showed that GABAA and GABAB receptors negatively regulate muscarinic receptor effects and interplay with cholinergic receptors to regulate free calcium ion levels for facial neural regeneration. 展开更多
关键词 injury of facial nerve γ-aminobutyric acid A receptor γ-aminobutyric acid B receptor muscarinic receptor facial nucleus calcium ion peripheral nerve injury neural regeneration
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Anisodine hydrobromide alleviates oxidative stress caused by hypoxia/reoxygenation in human cerebral microvascular endothelial cells predominantly via inhibition of muscarinic acetylcholine receptor 4
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作者 WENLI JIANG JUNYI SHEN +5 位作者 XIAOQIANG DU YAN QIU JIAN ZHONG ZHI OUYANG BINGMEI M.FU YE ZENG 《BIOCELL》 SCIE 2023年第10期2255-2263,共9页
Background:Anisodine hydrobromide(AT3),an anti-cholinergic agent,could be delivered to the brain across the blood-brain barrier and has been used clinically for the treatment of cerebral ischemia/reperfusion injury.En... Background:Anisodine hydrobromide(AT3),an anti-cholinergic agent,could be delivered to the brain across the blood-brain barrier and has been used clinically for the treatment of cerebral ischemia/reperfusion injury.Endothelial dysfunction can be caused by hypoxia/reoxygenation(H/R)via oxidative stress and metabolic alterations.The present study investigated whether AT3 regulates the production of nitric oxide(NO)and reactive oxygen species(ROS),and the HIF-1αpathway via regulation of muscarinic acetylcholine receptors(mAChRs)in brain microvascular endothelial cells after H/R exposure.Methods:Under H/R conditions,hCMEC/D3 cerebral microvascular endothelial cells were treated with AT3.Specific inhibitors of M2-and M4-mAChRs were used to explore the mechanism by which AT3 influences oxidative stress in endothelial cells.Then,mAChRs expression was detected by western blotting and NO production was detected by Greiss reaction.The intracellular ROS level was measured using DCFH-DA probes.The expression of hypoxia-inducible transcription factor 1α(HIF-1α)was also detected.Results:While H/R induced the expression of M2-and M4-mAChRs,AT3 suppressed the H/R-upregulated M2-and M4-mAChRs.H/R also induced the production of NO,ROS,and apoptosis.AT3 and M4-mAChR inhibitors inhibited the H/R-induced production of NO and ROS and apoptosis.HIF-1αwas induced by H/R,but was suppressed by AT3.Conclusion:Thus,the in vitro evidence shows that AT3 protects against H/R injury in cerebral microvascular endothelial cells via inhibition of HIF-1α,NO and ROS,predominantly through the downregulation of M4-mAChR.The findings offer novel understandings regarding AT3-mediated attenuation of endothelial cell apoptosis and cerebral ischemia/reperfusion injury. 展开更多
关键词 HYPOXIA/REOXYGENATION Endothelial cell Anisodine hydrobromide muscarinic acetylcholine receptors Hypoxia-inducible factor-1α
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Potencies of Four Stereoisomers of Anisodamine on Muscarinic Receptor 被引量:5
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作者 钮心懿 任志洪 谢兰 《Journal of Chinese Pharmaceutical Sciences》 CAS 1992年第2期81-86,共6页
用[3~H]-QNB配体受体结合实验,抗Ach对豚鼠回肠纵肌条收缩效应,抗毛果芸香碱流涎及扩瞳效应为指标,比较山莨菪碱四个立体异构体(A.6S,2′S;B.6S,2′R;C.6R,2′R;D.6R,2′S)与M受体相互作用的构效关系,结果A,B,C,D四个异构体效应分别为:... 用[3~H]-QNB配体受体结合实验,抗Ach对豚鼠回肠纵肌条收缩效应,抗毛果芸香碱流涎及扩瞳效应为指标,比较山莨菪碱四个立体异构体(A.6S,2′S;B.6S,2′R;C.6R,2′R;D.6R,2′S)与M受体相互作用的构效关系,结果A,B,C,D四个异构体效应分别为:(1)受体结合实验K_i(M)2.69×10^(-7),1.43×10^(-7),1.63×10^(-5),2.15×10^(-6);(2)抗Ach豚鼠回肠纵条收缩:K_6(M)2.98×10^(-8);1.38×10^(-8);1.52×10~5;1.0l×10^(-7);(3)扩瞳:ED_4(mol/kg)1.6×10^(-6),1.9×10^(-6),5.1×10^(-5),3.6×10^(-5);(4)抗毛果芸香碱流涎:ED_(50)(mol/kg)1.5×10^(-6);1.3×10^(-6);2.6×10^(-5);3.1×10^(-5)。以上结果表明四个异构体效应强度为6S,2′R≌6S,2′S>>6R,2′S>6R,2′R。 展开更多
关键词 ANISODAMINE STEREOISOMERS muscarinic receptor
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Microinjection of M_5 muscarinic receptor antisense oligonucleotide into VTA inhibits FosB expression in the NAc and the hippocampus of heroin sensitized rats
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作者 刘惠芬 周文华 +2 位作者 朱华强 赖苗军 陈为升 《Neuroscience Bulletin》 SCIE CAS CSCD 2007年第1期1-8,共8页
Objective To investigate the effect of M5 muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it's effect on the FosB expression in the nucleus accumbens (NAc) and the hippocam... Objective To investigate the effect of M5 muscarinic receptor subtype on the locomotor sensitization induced by heroin priming, and it's effect on the FosB expression in the nucleus accumbens (NAc) and the hippocampus in the heroin sensitized rats. Methods Locomotor activity was measured every 10 min for 1 h after subcutaneous injection of heroin. FosB expression was assayed by immunohistochemistry, and the antisense oligonucleotides (AS-ONs) targeting M5 muscarinic receptor was transferred with the lipofectin. Results Microinjection of AS-ONs targeting M5 muscarinic receptor in the ventral tegmental area (VTA) blocked the expression of behavioral sensitization induced by heroin priming in rats. Meanwhile, the expression of FosB-positive neurons in either the NAc or the dentate gyrus (DG) of the hippocam- pus increased in heroin-induced locomotor sensitized rats. The enhancement of FosB-positive neurons in the NAc or DG could be inhibited by microinjection of M5 muscarinic receptor AS-ONs into the VTA before the heroin-induced locomotor sensitization was performed. In contrast, microinjection of M5 muscarinic receptor sense oligonucleotide (S-ONs) into the VTA did not block the expression of behavioral sensitization or the expression of FosB in the NAc or DG in the heroin sensitized rats. Conclusion Blocking M5 muscarinic receptor in the VTA inhibits the expression of heroin-induced locomotor sensitization, which is associated with the regulation of FosB expression in the NAc and hippocampus neurons. M5 muscarinic receptor may be a useful pharmacological target for the treatment of heroin addiction. 展开更多
关键词 HEROIN locomotor activity muscarinic receptor FOSB nucleus accumbens HIPPOCAMPUS
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Brain-derived neurotrophic factor signaling in the neuromuscular junction during developmental axonal competition and synapse elimination
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作者 Josep Tomàs Víctor Cilleros-Mañé +7 位作者 Laia Just-Borràs Marta Balanyà-Segura Aleksandra Polishchuk Laura Nadal Marta Tomàs Carolina Silvera-Simón Manel M.Santafé Maria A.Lanuza 《Neural Regeneration Research》 SCIE CAS 2025年第2期394-401,共8页
During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their el... During the development of the nervous system,there is an overproduction of neurons and synapses.Hebbian competition between neighboring nerve endings and synapses performing different activity levels leads to their elimination or strengthening.We have extensively studied the involvement of the brain-derived neurotrophic factor-Tropomyosin-related kinase B receptor neurotrophic retrograde pathway,at the neuromuscular junction,in the axonal development and synapse elimination process versus the synapse consolidation.The purpose of this review is to describe the neurotrophic influence on developmental synapse elimination,in relation to other molecular pathways that we and others have found to regulate this process.In particular,we summarize our published results based on transmitter release analysis and axonal counts to show the different involvement of the presynaptic acetylcholine muscarinic autoreceptors,coupled to downstream serine-threonine protein kinases A and C(PKA and PKC)and voltage-gated calcium channels,at different nerve endings in developmental competition.The dynamic changes that occur simultaneously in several nerve terminals and synapses converge across a postsynaptic site,influence each other,and require careful studies to individualize the mechanisms of specific endings.We describe an activity-dependent balance(related to the extent of transmitter release)between the presynaptic muscarinic subtypes and the neurotrophin-mediated TrkB/p75NTR pathways that can influence the timing and fate of the competitive interactions between the different axon terminals.The downstream displacement of the PKA/PKC activity ratio to lower values,both in competing nerve terminals and at postsynaptic sites,plays a relevant role in controlling the elimination of supernumerary synapses.Finally,calcium entry through L-and P/Q-subtypes of voltage-gated calcium channels(both channels are present,together with the N-type channel in developing nerve terminals)contributes to reduce transmitter release and promote withdrawal of the most unfavorable nerve terminals during elimination(the weakest in acetylcholine release and those that have already become silent).The main findings contribute to a better understanding of punishment-rewarding interactions between nerve endings during development.Identifying the molecular targets and signaling pathways that allow synapse consolidation or withdrawal of synapses in different situations is important for potential therapies in neurodegenerative diseases. 展开更多
关键词 acetylcholine release adenosine receptors axonal competition brain-derived neurotrophic factor calcium channels motor end-plate muscarinic acetylcholine receptors postnatal synapse elimination serine kinases tropomyosin-related kinase receptorB
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Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes
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作者 Farfán-García Eunice Dalet Trujillo-Ferrara José Guadalupe +2 位作者 Castillo-Hernández María del Carmen Guerra-Araiza Christian Humberto Soriano-Ursúa Marvin Antonio 《Neural Regeneration Research》 SCIE CAS CSCD 2013年第24期2290-2302,共13页
In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of... In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selec- tivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and or- thosteric binding sites on dopamine receptors for the treatment of Parkinson's disease, and on muscarinic receptors for Alzheimer's disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopa- mine receptor holds promise as a relevant therapeutic strategy for Parkinson's disease. Regarding the treatment of Alzheimer's disease, the design of dualsteric ligands for mono-oligomeric mus- carinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway. 展开更多
关键词 neural regeneration G-Protein coupled receptors structural biology drug design neurodegenera-tive disorders oligomedzation biased signaling Parkinson's disease Alzheimer's disease dopa-mine receptors muscarinic receptors grants-supported paper NEUROREGENERATION
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AduoLa Fuzhenglin Down-regulates Microwave-induced Expression of β_1-adrenergic Receptor and Muscarinic Type 2 Acetylcholine Receptor in Myocardial Cells of Rats 被引量:9
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作者 ZHANG Jing PENG Rui Yun +7 位作者 GAO Ya Bing WANG Shui Ming YANG Lei Lei ZHAO Li DONG Ji YAO Bin Wei CHANG Gong Min XIONG Lu 《Biomedical and Environmental Sciences》 SCIE CAS CSCD 2014年第3期204-207,共4页
This paper is aimed to study the effect of ADL on expression of ~z-AR and Mz-AchR in myocardial cells of rats exposed to microwave radiation. Immunohistochemistry, Western blot and image analysis were used to detect t... This paper is aimed to study the effect of ADL on expression of ~z-AR and Mz-AchR in myocardial cells of rats exposed to microwave radiation. Immunohistochemistry, Western blot and image analysis were used to detect the expression of ~I-AR and Mz-AchR in myocardial cells at 7 and 14 d after microwave exposure. The results show that the expression level was higher in microwave exposure group and 0.75 g/(kg.d) ADL group than in sham operation group and significantly lower in 1.5 and 3.0 g/(kg.d) ADL groups than in microwave group. So we have a conclusion that the expression of I^z-AR and Mz-AchR is down-regulated in myocardial cells of rats exposed to microwave radiation. ADL can protect rats against microwave-induced heart tissue injury. 展开更多
关键词 AchR AduoLa Fuzhenglin Down-regulates Microwave-induced Expression of adrenergic Receptor and muscarinic Type 2 Acetylcholine Receptor in Myocardial Cells of Rats
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Muscarinic receptor-mediated calcium changes in a rat model of facial nerve nucleus injury 被引量:1
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作者 Dawei Sun Huamin Liu +5 位作者 Fugao Zhu Yanqing Wang Junfeng Wen Rui Zhou Yanjun Wang Banghua Liu 《Neural Regeneration Research》 SCIE CAS CSCD 2010年第18期1418-1422,共5页
The muscarinic receptor modulates intracellular free calcium ion levels in the facial nerve nucleus via different channels. In the present study, muscarinic receptor-mediated free calcium ions levels were detected by ... The muscarinic receptor modulates intracellular free calcium ion levels in the facial nerve nucleus via different channels. In the present study, muscarinic receptor-mediated free calcium ions levels were detected by confocal laser microscopy in the facial nerve nucleus following facial nerve injury in rats. There was no significant difference in muscarinic receptor expression at the affected facial nerve nucleus compared with expression prior to injury, but muscarinic receptor-mediated free calcium ion levels increased in the affected side following facial nerve injury (P 〈 0.01). At day 30 after facial nerve injury, 50 pmol/L muscarinic-mediated free calcium ion levels were significantly inhibited at the affected facial nerve nucleus in calcium-free artificial cerebrospinal fluid, and the change range was 82% of artificial cerebrospinal fluid (P 〈 0.05). These results suggest that increased free calcium ion concentrations are achieved by intracellular calcium ion release, and that the transmembrane flow of calcium ions is also involved in this process. 展开更多
关键词 facial nerve injury muscarinic receptor facial nerve nucleus calcium ion THAPSIGARGIN
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M3 Muscarinic Acetylcholine Receptor Antagonist Darifenacin Protects against Pulmonary Fibrosis through ERK/NF-κB/miR-21 Pathway 被引量:1
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作者 Ying Liu Yanan Jiang +2 位作者 Chao Wang Haiying Zhang Yan Liu 《American Journal of Molecular Biology》 2022年第2期11-22,共12页
Idiopathic pulmonary fibrosis is an untreatable lethal lung disease, which is related to the aberrant proliferation of fibroblasts. M<sub>3</sub> muscarinic acetylcholine receptor (M<sub>3</sub>... Idiopathic pulmonary fibrosis is an untreatable lethal lung disease, which is related to the aberrant proliferation of fibroblasts. M<sub>3</sub> muscarinic acetylcholine receptor (M<sub>3</sub>-mAChR) activation exerts proliferative effect on various kinds of cells. However, whether M<sub>3</sub>-mAChR inhibition has a protective effect on pulmonary fibrosis remains unexplored. A rat model of pulmonary fibrosis was established by intratracheal instillation of bleomycin. Darifenacin was used to block M<sub>3</sub>-mAChR. Histological changes were observed using Masson’s Trichrome and hematoxylin and eosin (HE) staining. Hydroxyproline was measured by Hydroxyproline detection kit. Transforming growth factor β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, pulmonary fibroblasts were isolated from lungs of neonatal rat. After treatment, the cell viability, Hydroxyproline level was measured by MTT and Hydroxyproline detection kit respectively. The expression level of extracellular signal-regulated kinase (ERK), nuclear factor kappa-B (N-NF-κB), and microRNA-21 (miR-21) was detected by western blot or quantitative real-time PCR (qRT-PCR). Darifenacin relieved the fibrotic effects provoked by bleomycin. The expression level of hydroxyproline, TGF-β1 and TNF-α level was all downregulated after darifenacin treatment. In lung fibroblasts, darifenacin decreased cell viability and hydroxyproline level induced by bleomycin. Besides, phosphorylation-ERK and nuclear N-NF-κB protein level was downregulated, as well as miR-21 level. M<sub>3</sub>-mAChR antagonist darifenacin attenuates bleomycin-induced pulmonary fibrosis in rats, which may relate to the ERK/NF-κB/miRNA-21 signaling pathway. 展开更多
关键词 Pulmonary Fibrosis M3 muscarinic Acetylcholine Receptor DARIFENACIN
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Muscarinic Acetylcholine Receptor Subtype Expression in Type Vestibular Hair Cells of Guinea Pigs
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作者 姚琦 程华茂 +3 位作者 郭长凯 周涛 黄翔 孔维佳 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2011年第5期682-686,共5页
Recent studies have demonstrated that five subtypes (M1-M5) of muscarinic acetylcholine receptor (mAChR) are expressed in the vestibular periphery. However, the exact cellular location of the mAChRs is not clear. ... Recent studies have demonstrated that five subtypes (M1-M5) of muscarinic acetylcholine receptor (mAChR) are expressed in the vestibular periphery. However, the exact cellular location of the mAChRs is not clear. In this study, we investigated whether there is the expression of M1-M5 muscarinic receptor mRNA in isolated type Ⅱ vestibular hair cells of guinea pig by using single-cell RT-PCR. In vestibular end-organ, cDNA of the expected size was obtained by RT-PCR. Moreover, mRNA was identified by RT-PCR from individually isolated type Ⅱ vestibular hair cells (single-cell RT-PCR). Sequence analysis confirmed that the products were M1-M5 mAChR. These results dem-onstrated that M1-M5 mAChR was expressed in the typeⅡvestibular hair cells of the guinea pig, which lends further support for the role of M1-M5 mAChR as a mediator of efferent cholinergic signalling pathway in vestibular hair cells. 展开更多
关键词 muscarinic acetylcholine receptor type vestibular hair cells single-cell RT-PCR
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Acupuncture at heterotopic acupoints enhances jejunal motility in constipated and diarrheic rats 被引量:11
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作者 Qing-Guang Qin Xin-Yan Gao +4 位作者 Kun Liu Xiao-Chun Yu Liang Li Hai-Ping Wang Bing Zhu 《World Journal of Gastroenterology》 SCIE CAS 2014年第48期18271-18283,共13页
AIM: To investigate the effect and mechanism of acupuncture at heterotopic acupoints on jejunal motility, particularly in pathological conditions.
关键词 ACUPUNCTURE Heterotopic acupoint LI11 ST37 BL25 Jejunal motility CONSTIPATION Diarrhea C fibers muscarinic receptors
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Multiple roles for cholinergic signaling in pancreatic diseases
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作者 Jun-Min Yang Xiao-Yu Yang Jian-Hua Wan 《World Journal of Gastroenterology》 SCIE CAS 2022年第25期2910-2919,共10页
Cholinergic nerves are widely distributed throughout the human body and participate in various physiological activities,including sensory,motor,and visceral activities,through cholinergic signaling.Cholinergic signali... Cholinergic nerves are widely distributed throughout the human body and participate in various physiological activities,including sensory,motor,and visceral activities,through cholinergic signaling.Cholinergic signaling plays an important role in pancreatic exocrine secretion.A large number of studies have found that cholinergic signaling overstimulates pancreatic acinar cells through muscarinic receptors,participates in the onset of pancreatic diseases such as acute pancreatitis and chronic pancreatitis,and can also inhibit the progression of pancreatic cancer.However,cholinergic signaling plays a role in reducing pain and inflammation through nicotinic receptors,but enhances the proliferation and invasion of pancreatic tumor cells.This review focuses on the progression of cholinergic signaling and pancreatic diseases in recent years and reveals the role of cholinergic signaling in pancreatic diseases. 展开更多
关键词 ACETYLCHOLINE muscarinic receptors Nicotinic receptors Pancreatic exocrine PANCREATITIS Pancreatic cancer
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Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats 被引量:4
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作者 HelenaFWrzos TarunTandon AnnOuyang 《World Journal of Gastroenterology》 SCIE CAS CSCD 2004年第22期3292-3298,共7页
AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction... AIM:To investigate the pathway(s)mediating rat antral circular smooth muscle contractile responses to the cholinomimetic agent,bethanechol and the subtypes of muscarinic receptors mediating the cholinergic contraction. METHODS:Circular smooth muscle strips from the antrum of Sprague-Dawley rats were mounted in muscle baths in Krebs buffer.Isometric tension was recorded.Cumulative concentration-response curves were obtained for(+)-cis- dioxolane(cD),a nonspecific muscarinic agonist,at 10^(-8)- 10^(-4)mol/L,in the presence of tetrodotoxin(TTX,10^(-7)mol/L). Results were normalized to cross sectional area.A repeat concentration-response curve was obtained after incubation of the muscle for 90 min with antagonists for M1(pirenzepine), M2(methoctramine)and M3(darifenadn)muscarinic receptor subtypes.The sensitivity to PTX was tested by the ip injection of 100 mg/kg of PTX 5 d before the experiment.The antral circular smooth muscles were removed from PTX-treated and non-treated rats as strips and dispersed smooth muscle cells to identify whether PTX-linked pathway mediated the contractility to bethanechol. RESULTS:A dose-dependent contractile response observed with bethanechol,was not affected by TTx.The pretreatment of rats with pertussis toxin decreased the contraction induced by bethanechol.Lack of calcium as well as the presence of the L-type calcium channel blocker,nifedipine,also inhibited the cholinergic contraction,with a reduction in response from 2.5±0.4 g/mm^2 to 1.2±0.4 g/mm^2(P<0.05).The dose- response curves were shifted to the right by muscarinic antagonists in the following order of affinity:darifenacin (M_3)>methocramine(M_2)>pirenzepine(M_1). CONCLUSION:The muscarinic receptors-dependent contraction of rat antral circular smooth muscles was linked to the signal transduction pathway(s)involving pertussis-toxin sensitive GTP-binding proteins and to extracellular calcium via L-type voltage gated calcium channels.The presence of the residual contractile response after the treatment with nifedipine,suggests that an additional pathway could mediate the cholinergic contraction.The involvement of more than one muscarinic receptor(functionally predominant type 3 over type 2)also suggests more than one pathway mediating the cholinergic contraction in rat antrum. 展开更多
关键词 Anesthetics Local Animals BENZOFURANS BETHANECHOL Calcium Calcium Channel Blockers Cholinergic Agonists Dose-Response Relationship Drug GTP-Binding Proteins In Vitro Male muscarinic Antagonists Muscle Contraction Muscle Smooth Nifedipine Pertussis Toxin Pirenzepine Pyloric Antrum PYRROLIDINES RATS Rats Sprague-Dawley Receptor muscarinic M1 inhibitors Receptor muscarinic M2 Receptor muscarinic M3 Signal Transduction Tetrodotoxin
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Beauty of the beast: anticholinergic tropane alkaloids in therapeutics 被引量:2
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作者 Kyu Hwan Shim Min Ju Kang +1 位作者 Niti Sharma Seong Soo A.An 《Natural Products and Bioprospecting》 2022年第1期515-529,共15页
Tropane alkaloids(TAs)are among the most valued chemical compounds known since pre-historic times.Poisonous plants from Solanaceae family(Hyoscyamus niger,Datura,Atropa belladonna,Scopolia lurida,Mandragora officinaru... Tropane alkaloids(TAs)are among the most valued chemical compounds known since pre-historic times.Poisonous plants from Solanaceae family(Hyoscyamus niger,Datura,Atropa belladonna,Scopolia lurida,Mandragora officinarum,Duboisia)and Erythroxylaceae(Erythroxylum coca)are rich sources of tropane alkaloids.These compounds possess the anticholinergic properties as they could block the neurotransmitter acetylcholine action in the central and peripheral nervous system by binding at either muscarinic and/or nicotinic receptors.Hence,they are of great clinical impor-tance and are used as antiemetics,anesthetics,antispasmodics,bronchodilator and mydriatics.They also serve as the lead compounds to generate more effective drugs.Due to the important pharmacological action they are listed in the WHO list of essential medicines and are available in market with FDA approval.However,being anticholinergic in action,TA medication are under the suspicion of causing dementia and cognitive decline like other medications with anticholinergic action,interestingly which is incorrect.There are published reviews on chemistry,biosynthesis,phar-macology,safety concerns,biotechnological aspects of TAs but the detailed information on anticholinergic mecha-nism of action,clinical pharmacology,FDA approval and anticholinergic burden is lacking.Hence the present review tries to fill this lacuna by critically summarizing and discussing the above mentioned aspects. 展开更多
关键词 Tropane alkaloids Poisonous plants Anticholinergic action muscarinic and nicotinic receptors THERAPEUTICS Anticholinergic burden
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