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nAChRs

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https://www.readbyqxmd.com/read/27917874/discovery-synthesis-biological-evaluation-and-structure-based-optimization-of-novel-piperidine-derivatives-as-acetylcholine-binding-protein-ligands
#1
Jian Shen, Xi-Cheng Yang, Ming-Cheng Yu, Li Xiao, Xun-Jie Zhang, Hui-Jiao Sun, Hao Chen, Guan-Xin Pan, Yu-Rong Yan, Si-Chen Wang, Wei Li, Lu Zhou, Qiong Xie, Lin-Qian Yu, Yong-Hui Wang, Li-Ming Shao
The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChR-ligand interactions, and to identify ligands with potential nAChR-like activities...
December 5, 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27914011/activation-of-alpha-7-nicotinic-acetylcholine-receptor-reduces-brain-edema-in-mice-with-ischemic-stroke-and-bone-fracture
#2
Dingquan Zou, Man Luo, Zhenying Han, Lei Zhan, Wan Zhu, Shuai Kang, Chen Bao, Zhao Li, Jeffrey Nelson, Rui Zhang, Hua Su
Stroke is an important risk factor for bone fracture. We showed previously that bone fracture at the acute stage of ischemic stroke worsens, and activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) improves, stroke recovery by attenuating inflammation. We hypothesized that activation of α-7 nAchR also improves the blood-brain barrier (BBB) integrity. Permanent distal middle cerebral artery occlusion (pMCAO) was performed on C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated with 0...
December 2, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27911815/nicotinic-receptors-in-mouse-prefrontal-cortex-modulate-ultraslow-fluctuations-related-to-conscious-processing
#3
Fani Koukouli, Marie Rooy, Jean-Pierre Changeux, Uwe Maskos
The prefrontal cortex (PFC) plays an important role in cognitive processes, including access to consciousness. The PFC receives significant cholinergic innervation and nicotinic acetylcholine receptors (nAChRs) contribute greatly to the effects of acetylcholine signaling. Using in vivo two-photon imaging of both awake and anesthetized mice, we recorded spontaneous, ongoing neuronal activity in layer II/III in the PFC of WT mice and mice deleted for different nAChR subunits. As in humans, this activity is characterized by synchronous ultraslow fluctuations and neuronal synchronicity is disrupted by light general anesthesia...
December 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27908269/levamisole-a-positive-allosteric-modulator-for-the-%C3%AE-3%C3%AE-4-nicotinic-acetylcholine-receptors-prevents-weight-gain-in-cd-1-mice-on-a-high-fat-diet
#4
Jeanne A Lewis, Jerrel L Yakel, Anshul A Pandya
Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the function of multiple neurotransmitter pathways throughout the central nervous system. This includes nAChRs found on the proopiomelanocortin neurons in the hypothalamus. Activation of these nAChRs by nicotine causes a decrease in consumption of food in rodents. In this study, we tested the effect of subtype selective allosteric modulators for nAChRs on the body weight of CD-1 mice. Levamisole, an allosteric modulator for the α3β4 subtype of nAChRs, prevented weight gain in mice that were fed a high fat diet...
December 1, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27907022/nicotine-induces-podocyte-apoptosis-through-increasing-oxidative-stress
#5
Xiqian Lan, Rivka Lederman, Judith M Eng, Seyedeh Shadafarin Marashi Shoshtari, Moin A Saleem, Ashwani Malhotra, Pravin C Singhal
BACKGROUND: Cigarette smoking plays an important role in the progression of chronic kidney disease (CKD). Nicotine, one of the major components of cigarette smoking, has been demonstrated to increase proliferation of renal mesangial cells. In this study, we examined the effect of nicotine on podocyte injury. METHODS: To determine the expression of nicotinic acetylcholine receptors (nAChR subunits) in podocytes, cDNAs and cell lysate of cultured human podocytes were used for the expression of nAChR mRNAs and proteins, respectively; and mouse renal cortical sections were subjected to immunofluorescant staining...
2016: PloS One
https://www.readbyqxmd.com/read/27901080/block-of-nicotinic-acetylcholine-receptors-by-philanthotoxins-is-strongly-dependent-on-their-subunit-composition
#6
Hamid S Kachel, Rohit N Patel, Henrik Franzyk, Ian R Mellor
Philanthotoxin-433 (PhTX-433) is an active component of the venom from the Egyptian digger wasp, Philanthus triangulum. PhTX-433 inhibits several excitatory ligand-gated ion channels, and to improve selectivity two synthetic analogues, PhTX-343 and PhTX-12, were developed. Previous work showed a 22-fold selectivity of PhTX-12 over PhTX-343 for embryonic muscle-type nicotinic acetylcholine receptors (nAChRs) in TE671 cells. We investigated their inhibition of different neuronal nAChR subunit combinations as well as of embryonic muscle receptors expressed in Xenopus oocytes...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27886263/nicotinic-and-opioid-receptor-regulation-of-striatal-dopamine-d2-receptor-mediated-transmission
#7
Aphroditi A Mamaligas, Yuan Cai, Christopher P Ford
In addition to dopamine neuron firing, cholinergic interneurons (ChIs) regulate dopamine release in the striatum via presynaptic nicotinic receptors (nAChRs) on dopamine axon terminals. Synchronous activity of ChIs is necessary to evoke dopamine release through this pathway. The frequency-dependence of disynaptic nicotinic modulation has led to the hypothesis that nAChRs act as a high-pass filter in the dopaminergic microcircuit. Here, we used optogenetics to selectively stimulate either ChIs or dopamine terminals directly in the striatum...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27871840/probing-the-structure-of-the-uncoupled-nicotinic-acetylcholine-receptor
#8
Jiayin Sun, J Frederique Comeau, John E Baenziger
In the absence of activating anionic lipids and cholesterol, the nicotinic acetylcholine receptor (nAChR) from Torpedo adopts an uncoupled conformation that does not usually gate open in response to agonist. The uncoupled conformation binds both agonists and non-competitive channel blockers with a lower affinity than the desensitized state, consistent with both the extracellular agonist-binding and transmembrane channel-gating domains individually adopting resting-state like conformations. To test this hypothesis, we characterized the binding of the agonist, acetylcholine, and two fluorescent channel blockers, ethidium and crystal violet, to resting, desensitized and uncoupled nAChRs in reconstituted membranes...
November 19, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27871728/the-chrna5-a3-b4-gene-cluster-and-smoking-from-discovery-to-therapeutics
#9
REVIEW
Glenda Lassi, Amy E Taylor, Nicholas J Timpson, Paul J Kenny, Robert J Mather, Tim Eisen, Marcus R Munafò
Genome-wide association studies (GWASs) have identified associations between the CHRNA5-CHRNA3-CHRNB4 gene cluster and smoking heaviness and nicotine dependence. Studies in rodents have described the anatomical localisation and function of the nicotinic acetylcholine receptors (nAChRs) formed by the subunits encoded by this gene cluster. Further investigations that complemented these studies highlighted the variability of individuals' smoking behaviours and their ability to adjust nicotine intake. GWASs of smoking-related health outcomes have also identified this signal in the CHRNA5-CHRNA3-CHRNB4 gene cluster...
November 18, 2016: Trends in Neurosciences
https://www.readbyqxmd.com/read/27866776/activation-of-%C3%AE-7-nicotinic-acetylcholine-receptors-facilitates-long-term-potentiation-at-the-hippocampal-prefrontal-cortex-synapses-in-vivo
#10
Milan Stoiljkovic, Craig Kelley, Dávid Nagy, Raymond Hurst, Mihály Hajós
Activation of α7 nAChRs has been shown to improve performance in a variety of nonclinical assays of cognitive function. The role of α7 nAChRs in cognitive processes is likely related to their role in modulating synaptic transmission and plasticity that have been reported in cell culture, brain slices, and intact animals. Here we report the effects of the α7 nAChR agonist FRM-17874 on synaptic plasticity within the hippocampal-medial prefrontal cortex pathway. Long-term potentiation (LTP) was generated by tetanic stimulation of CA1/subiculum region in urethane anesthetized male rats...
December 2016: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/27865910/multi-target-directed-therapeutic-potential-of-7-methoxytacrine-adamantylamine-heterodimers-in-the-alzheimer-s-disease-treatment
#11
Zuzana Gazova, Ondrej Soukup, Vendula Sepsova, Katarina Siposova, Lucie Drtinova, Petr Jost, Katarina Spilovska, Jan Korabecny, Eugenie Nepovimova, Diana Fedunova, Martin Horak, Martina Kaniakova, Ze-Jun Wang, Ayman K Hamouda, Kamil Kuca
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory...
November 16, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27864368/role-of-the-cys-loop-and-transmembrane-domain-in-the-allosteric-modulation-of-%C3%AE-4%C3%AE-2-nicotinic-acetylcholine-receptors
#12
Constanza Alcaino, Maria Musgaard, Teresa Minguez, Simone Mazzaferro, Manuel Faundez, Patricio Iturriaga-Vasquez, Philip C Biggin, Isabel Bermudez
Allosteric modulators of pentameric ligand gated ion channels (pLGICs) are thought to act on elements of the pathways that couple agonist binding to channel gating. Using α4β2 nicotinic acetylcholine receptors (nAChRs) and the α4β2-selective positive modulators 17β-estradiol (βEST) and desformylflustrabromine (dFBr), we have identified pathways that link the binding sites for these modulators to the Cys loop, a region that is critical for channel gating in all pLGICs. Previous studies have shown that the binding site for potentiating βEST is in the C-terminal (post-M4 region) of the α4 subunit...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27856558/human-polymorphisms-in-nicotinic-receptors-a-functional-analysis-in-ips-derived-dopaminergic-neurons
#13
Cristina Deflorio, Stéphane Blanchard, Maria Carla Carisì, Delphine Bohl, Uwe Maskos
Tobacco smoking is a public health problem, with ∼5 million deaths per year, representing a heavy burden for many countries. No effective therapeutic strategies are currently available for nicotine addiction, and it is therefore crucial to understand the etiological and pathophysiological factors contributing to this addiction. The neuronal α5 nicotinic acetylcholine receptor (nAChR) subunit is critically involved in nicotine dependence. In particular, the human polymorphism α5D398N corresponds to the strongest correlation with nicotine dependence risk found to date in occidental populations, according to meta-analysis of genome-wide association studies...
November 17, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27846263/nicotine-induced-effects-on-nicotinic-acetylcholine-receptors-nachrs-ca2-and-brain-derived-neurotrophic-factor-bdnf-in-stc-1-cells
#14
Jie Qian, Shobha K Mummalaneni, Reem M Alkahtani, Sunila Mahavadi, Karnam S Murthy, John R Grider, Vijay Lyall
In addition to the T2R bitter taste receptors, neuronal nicotinic acetylcholine receptors (nAChRs) have recently been shown to be involved in the bitter taste transduction of nicotine, acetylcholine and ethanol. However, at present it is not clear if nAChRs are expressed in enteroendocrine cells other than beta cells of the pancreas and enterochromaffin cells, and if they play a role in the synthesis and release of neurohumoral peptides. Accordingly, we investigated the expression and functional role of nAChRs in enteroendocrine STC-1 cells...
2016: PloS One
https://www.readbyqxmd.com/read/27844094/attenuation-of-nicotine-taking-and-seeking-in-rats-by-the-stoichiometry-selective-alpha4beta2-nicotinic-acetylcholine-receptor-positive-allosteric-modulator-ns9283
#15
John J Maurer, Karin Sandager-Nielsen, Heath D Schmidt
RATIONALE: The rewarding and reinforcing effects of nicotine are produced, in large part, by activation of neuronal α4β2* nicotinic acetylcholine receptors (nAChRs), pentameric protein complexes comprised of different stoichiometries of α4 and β2 subunits. However, little is known about the functional role of distinct subtypes of α4β2* nAChRs in nicotine addiction. OBJECTIVES: NS9283 represents a new class of stoichiometry-selective positive allosteric modulators (PAMs) that selectively bind to α4β2 nAChRs containing three α4 and two β2 subunits (3(α4)2(β2) nAChRs)...
November 14, 2016: Psychopharmacology
https://www.readbyqxmd.com/read/27834303/single-nucleotide-polymorphisms-and-genotypes-of-transient-receptor-potential-ion-channel-and-acetylcholine-receptor-genes-from-isolated-b-lymphocytes-in-myalgic-encephalomyelitis-chronic-fatigue-syndrome-patients
#16
Sonya Marshall-Gradisnik, Samantha Johnston, Anu Chacko, Thao Nguyen, Peter Smith, Donald Staines
OBJECTIVE: The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca(2+)) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients...
November 10, 2016: Journal of International Medical Research
https://www.readbyqxmd.com/read/27827986/replicated-risk-nicotinic-cholinergic-receptor-genes-for-nicotine-dependence
#17
Lingjun Zuo, Rolando Garcia-Milian, Xiaoyun Guo, Chunlong Zhong, Yunlong Tan, Zhiren Wang, Jijun Wang, Xiaoping Wang, Longli Kang, Lu Lu, Xiangning Chen, Chiang-Shan R Li, Xingguang Luo
It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses...
November 7, 2016: Genes
https://www.readbyqxmd.com/read/27821848/depression-like-phenotype-by-deletion-of-%C3%AE-7-nicotinic-acetylcholine-receptor-role-of-bdnf-trkb-in-nucleus-accumbens
#18
Ji-Chun Zhang, Wei Yao, Qian Ren, Chun Yang, Chao Dong, Min Ma, Jin Wu, Kenji Hashimoto
The α7 subtype of nicotinic acetylcholine receptor (nAChR) plays a role in the inflammation which is implicated in depression. This study was undertaken to examine the role of α7 nAChR in depression using α7 nAChR knock-out (KO) mice. Serum levels of tumor necrosis factor-α and interlukin-1β in KO mice were higher than wild-type mice, suggesting an inflammatory process in KO mice. α7 nAChR KO mice showed depression-like phenotype. Furthermore, KO mice showed increased brain-derived neurotrophic factor (BDNF) and its receptor TrkB signaling, as well as increased synaptogenesis and spine density in the nucleus accumbens (NAc), although BDNF-TrkB signaling and synaptogenesis were not altered in the prefrontal cortex and hippocampus...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27818109/novel-5-substituted-3-hydroxyphenyl-and-3-nitrophenyl-ethers-of-s-prolinol-as-%C3%AE-4%C3%AE-2-nicotinic-acetylcholine-receptor-ligands
#19
Cristiano Bolchi, Francesco Bavo, Laura Fumagalli, Cecilia Gotti, Francesca Fasoli, Milena Moretti, Marco Pallavicini
A series of 3-nitrophenyl and 3-hydroxyphenyl ethers of (S)-N-methylprolinol bearing bulky and lipophilic substituents at phenyl C5 were tested for affinity at α4β2 and α3β4 nAChRs. The two phenyl ethers 5-substituted with 6-hydroxy-1-hexynyl showed high α4β2 affinity and significantly increased α4β2/α3β4 selectivity compared to the respective unsubstituted parent compounds. Within the two series of novel phenyl ethers, we observed parallel shifts in affinity and, furthermore, the increase in α4β2/α3β4 selectivity resulting from the hydroxyalkynyl substitution parallels that reported for the same modification at the 3-pyridyl ether of (S)-N-methylprolinol (A-84543), a well-known potent α4β2 agonist...
October 27, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27817023/analysis-of-binding-centers-in-nicotinic-receptors-with-the-aid-of-synthetic-peptides
#20
I E Kasheverov, E V Kryukova, D S Kudryavtsev, I A Ivanov, N V Egorova, M N Zhmak, E N Spirova, I V Shelukhina, A V Odinokov, M V Alfimov, V I Tsetlin
We studies the receptor-binding specificity of the synthetic peptide HAP (High Affinity Peptide) and its analogues, which are regarded as a model of the orthosteric site nicotinic acetylcholine receptors (nAChR). Using radioligand analysis, electrophysiology tests, and calcium imaging, we assessed the ability of HAP to interact with nAChR antagonists: long α-neurotoxins and α-conotoxins. A high affinity of HAP for α-bungarotoxin and the absence of its interaction with α-cobratoxin and α-conotoxins was found...
September 2016: Doklady. Biochemistry and Biophysics
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