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https://www.readbyqxmd.com/read/28623170/nicotinic-acetylcholine-receptor-inhibitors-derived-from-snake-and-snail-venoms
#1
REVIEW
Sebastien Dutertre, Annette Nicke, Victor Tsetlin
The nicotinic acetylcholine receptor (nAChR) represents the prototype of ligand-gated ion channels. It is vital for neuromuscular transmission and an important regulator of neurotransmission. A variety of toxic compounds derived from diverse species target this receptor and have been of elemental importance in basic and applied research. They enabled milestone discoveries in pharmacology and biochemistry ranging from the original formulation of the receptor concept, the first isolation and structural analysis of a receptor protein (the nAChR) to the identification, localization, and differentiation of its diverse subtypes and their validation as a target for therapeutic intervention...
June 13, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28611586/the-distribution-of-charged-amino-acid-residues-and-the-ca-2-permeability-of-nicotinic-acetylcholine-receptors-a-predictive-model
#2
Sergio Fucile
Nicotinic acetylcholine receptors (nAChRs) are cation-selective ligand-gated ion channels exhibiting variable Ca(2+) permeability depending on their subunit composition. The Ca(2+) permeability is a crucial functional parameter to understand the physiological role of nAChRs, in particular considering their ability to modulate Ca(2+)-dependent processes such as neurotransmitter release. The rings of extracellular and intracellular charged amino acid residues adjacent to the pore-lining TM2 transmembrane segment have been shown to play a key role in the cation selectivity of these receptor channels, but to date a quantitative relationship between these structural determinants and the Ca(2+) permeability of nAChRs is lacking...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28607408/differences-in-pharmacodynamic-responses-to-rocuronium-in-normal-or-injured-orbicularis-oris-are-associated-with-expression-of-acetylcholine-receptor-subunits
#3
Yong Huang, Yian Xing, Hong Wang, Lianhua Chen, Shitong Li
Previous research has indicated that differences in sensitivities to muscle relaxants exist between facial nerve- and somatic nerve-innervated muscles. Here, we report that the 50% inhibitory concentration (IC50) values for rocuronium were significantly larger in the normal orbicularis oris than those in the gastrocnemius. Increased IC50 values and reduced twitch tension were observed after facial nerve injury. The normal orbicularis oris had a smaller muscle fiber cross-sectional area (CSA) and a larger ratio of endplate surface area (ESA) to muscle fiber CSA (ESA/CSA), but no difference was found in the density of nicotinic acetylcholine receptor (nAChR) subunits on endplates between normal orbicularis oris and gastrocnemius...
June 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28606760/progress-in-the-discovery-of-small-molecule-modulators-of-the-cys-loop-superfamily-receptors
#4
REVIEW
Brian A Sparling, Erin F DiMauro
The vertebrate Cys-loop family of ligand-gated ion channels (LGICs) are comprised of nicotinic acetylcholine (nAChR), serotonin type 3 (5-HT3R), γ-aminobutyric acid (GABAAR), and glycine (GlyR) receptors. Here, we review efforts to discover selective small molecules targeting one or more Cys-loop receptors, with a focus on state-of-the-art modulators that have been reported over the past five years. Several highlighted compounds offer robust oral bioavailability and central exposure and have thus been useful in delineating pharmacokinetic/pharmacodynamic relationships in pre-clinical disease models...
May 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28606623/the-interaction-between-alpha-7-nicotinic-acetylcholine-receptor-and-nuclear-peroxisome-proliferator-activated-receptor-%C3%AE-represents-a-new-antinociceptive-signaling-pathway-in-mice
#5
Giulia Donvito, Deniz Bagdas, Wisam Toma, Elnaz Rahimpour, Asti Jackson, Julie A Meade, Shakir AlSharari, Abhijit R Kulkarni, F Ivy Carroll, Aron H Lichtman, Roger L Papke, Ganesh A Thakur, M Imad Damaj
Recently, α7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti-inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago-allosteric ligands (ago-PAMs), and α7-silent agonists. Activation of α7 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator-activated receptors type-α (PPAR-α), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca(2+)-dependent manner...
June 9, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28603989/%C3%AE-conotoxin-s9a-txid-potently-discriminates-between-%C3%AE-3%C3%AE-4-and-%C3%AE-6-%C3%AE-3%C3%AE-4-nicotinic-acetylcholine-receptors
#6
Yong Wu, Dongting Zhangsun, Xiaopeng Zhu, Quentin Kaas, Manqi Zhangsun, Peta J Harvey, David J Craik, J Michael McIntosh, Sulan Luo
α3β4 nAChRs have been implicated in various pathophysiological conditions. However, the expression profile of α3β4 nAChRs and α6/α3β4 nAChRs overlap in a variety of tissues. To distinguish between these two subtypes, we redesigned peptide 1 (α-conotoxin TxID), which inhibits α3β4 and α6/α3β4 nAChR subtypes. We systematically mutated 1 to evaluate analogue selectivity for α3β4 vs α6/α3β4 nAChRs expressed in Xenopus laevis oocytes. One analogue, peptide 7 ([S9A]TxID), had 46-fold greater potency for α3β4 versus α6/α3β4 nAChRs...
June 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28602809/potential-of-%C3%AE-7-nachr-pet-imaging-in-atherosclerosis
#7
REVIEW
P F Ellen Boswijk, Matthias Bauwens, Felix M Mottaghy, Joachim E Wildberger, Jan Bucerius
Atherosclerotic events are usually acute and often strike otherwise asymptomatic patients. Although multiple clinical risk factors have been associated with atherosclerosis up to date, no further individual prediction can be made as to who will acutely suffer from its consequences based on traditional imaging methods like CT, MRI or angiography, or biomarkers. Previously, non-invasive imaging with (18)F-fluorodeoxyglucose ((18)F-FDG) PET was shown to potentially fill this niche as it offers high sensitive detection of metabolic processes associated with inflammatory changes in atherosclerotic plaques...
June 7, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28600847/the-fifth-subunit-of-the-%C3%AE-4%C3%AE-2-2-%C3%AE-2-nicotinic-acetylcholine-receptor-modulates-maximal-ach-responses
#8
Karina New, Silvia Garcia Del Villar, Simone Mazzaferro, Constanza Alcaino, Isabel Bermudez
BACKGROUND AND PURPOSE: The fifth subunit in the (α4β2)2 α4 nicotinic acetylcholine receptor (nAChR) plays a determining role in the pharmacology of this nAChR type. Here, we have examined the role of the fifth subunit in the ACh responses of the (α4β2)2 β2 nAChR type. EXPERIMENTAL APPROACH: The role of the fifth subunit in receptor function was explored using two-electrode voltage-clamp electrophysiology, along with subunit-targeted mutagenesis and the substituted cysteine scanning method applied to fully linked (α4β2)2 β2 receptors...
June 10, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28598389/identification-of-a-novel-o-conotoxin-reveals-an-unusual-and-potent-inhibitor-of-the-human-%C3%AE-9%C3%AE-10-nicotinic-acetylcholine-receptor
#9
Shantong Jiang, Han-Shen Tae, Shaoqiong Xu, Xiaoxia Shao, David J Adams, Chunguang Wang
Conotoxins are a pool of disulfide-rich peptide neurotoxins produced by cone snails for predation and defense. They are a rich reservoir of novel ligands for ion channels, neurotransmitter receptors and transporters in the nervous system. In this study, we identified a novel conotoxin component, O-conotoxin GeXXVIIA, from the venom of Conus generalis. The native form of this component is a disulfide-linked homodimer of a 5-Cys-containing peptide. Surprisingly, our electrophysiological studies showed that, in comparison to the folded monomers, the linear peptide of this toxin had the highest inhibitory activity at the human α9α10 nicotinic acetylcholine receptor (nAChR), with an IC50 of 16...
June 9, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28589175/secondary-ammonium-agonists-make-dual-cation-%C3%AF-interactions-in-%C3%AE-4%C3%AE-2-nicotinic-receptors
#10
Michael R Post, Gabrielle S Tender, Henry A Lester, Dennis A Dougherty
A cation-π interaction between the ammonium group of an agonist and a conserved tryptophan termed TrpB is a near universal feature of agonist binding to nicotinic acetylcholine receptors (nAChRs). TrpB is one of five residues that form the aromatic box of the agonist binding site, and for the prototype agonists ACh and nicotine, only TrpB makes a functional cation-π interaction. We report that, in addition to TrpB, a significant cation-π interaction is made to a second aromatic, TyrC2, by the agonists metanicotine, TC299423, varenicline, and nornicotine...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28587231/a-novel-lid-covering-peptide-inhibitor-of-nicotinic-acetylcholine-receptors-derived-from-%C3%AE-d-conotoxin-gexxa
#11
Longjin Yang, Han-Shen Tae, Zhou Fan, Xiaoxia Shao, Shaoqiong Xu, Suwen Zhao, David J Adams, Chunguang Wang
Nicotinic acetylcholine receptors (nAChRs) play a fundamental role in nervous signal transmission, therefore various antagonists and agonists are highly desired to explore the structure and function of nAChRs. Recently, a novel dimeric αD-conotoxin GeXXA was identified to inhibit nAChRs by binding at the top surface of the receptors, and the monomeric C-terminal domain (CTD) of αD-GeXXA retains some inhibitory activity. In this study, the internal dimeric N-terminal domain (NTD) of this conopeptide was further investigated...
June 5, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28586306/revisiting-nicotine-s-role-in-the-ageing-brain-and-cognitive-impairment
#12
Alireza Majdi, Farzin Kamari, Manouchehr Seyedi Vafaee, Saeed Sadigh-Eteghad
Brain ageing is a complex process which in its pathologic form is associated with learning and memory dysfunction or cognitive impairment. During ageing, changes in cholinergic innervations and reduced acetylcholinergic tonus may trigger a series of molecular pathways participating in oxidative stress, excitotoxicity, amyloid-β toxicity, apoptosis, neuroinflammation, and perturb neurotrophic factors in the brain. Nicotine is an exogenous agonist of nicotinic acetylcholine receptors (nAChRs) and acts as a pharmacological chaperone in the regulation of nAChR expression, potentially intervening in age-related changes in diverse molecular pathways leading to pathology...
June 6, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/28585699/impact-of-aging-on-postsynaptic-neuronal-nicotinic-neurotransmission-in-auditory-thalamus
#13
Sarah Y Sottile, Lynne Ling, Brandon C Cox, Donald M Caspary
The flow of auditory information through the medial geniculate body (MGB) is regulated, in part, by cholinergic projections from the pontomesencephalic tegmentum (PMT). The functional significance of these projections is not fully established, but they have been strongly implicated in the allocation of auditory attention. Using in vitro slice recordings, we have analysed postsynaptic function and pharmacology of neuronal nicotinic acetylcholine receptors (nAChRs) in young adult and aged rat MGB. We find that acetylcholine produces significant excitatory postsynaptic actions on young MGB neurons, likely mediated by β2-containing heteromeric nAChRs...
June 6, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28585241/reduced-%C3%AE-4-subunit-expression-in-%C3%AE-4-and-%C3%AE-4-%C3%AE-2-genotypes-alters-the-extent-of-%C3%AE-4%C3%AE-2-subtype-up-regulation-in-response-to-chronic-nicotine-treatment
#14
M Moretti, F Fasoli, C Gotti, Michael J Marks
BACKGROUND AND PURPOSE: Genomic studies have demonstrated the existence of many variants in both CHRNA4 and CHRNB2, which encode the α4 and β2 of nicotinic acetylcholine receptor (nAChR) subunits, respectively; some variants influence receptor expression raising the possibility that CHRNA4 variants may affect response to tobacco use in humans. Chronic nicotine exposure increases (up-regulates) expression of nAChRs, particularly the α4β2-nAChR subtype, in humans and laboratory animals and our purpose was to evaluate whether initial level of receptor expression influences amount of up-regulation...
June 5, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28585176/the-crystal-structure-of-ac-achbp-in-complex-with-%C3%AE-conotoxin-lvia-reveals-the-mechanism-of-its-selectivity-towards-different-nachr-subtypes
#15
Manyu Xu, Xiaopeng Zhu, Jinfang Yu, Jinpeng Yu, Sulan Luo, Xinquan Wang
The α3* nAChRs, which are considered to be promising drug targets for problems such as pain, addiction, cardiovascular function, cognitive disorders etc., are found throughout the central and peripheral nervous system. The α-conotoxin (α-CTx) LvIA has been identified as the most selective inhibitor of α3β2 nAChRs known to date, and it can distinguish the α3β2 nAChR subtype from the α6/α3β2β3 and α3β4 nAChR subtypes. However, the mechanism of its selectivity towards α3β2, α6/α3β2β3, and α3β4 nAChRs remains elusive...
June 5, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28583088/uncovering-the-transcriptomic-and-epigenomic-landscape-of-nicotinic-receptor-genes-in-non-neuronal-tissues
#16
Bo Zhang, Pamela Madden, Junchen Gu, Xiaoyun Xing, Savita Sankar, Jennifer Flynn, Kristen Kroll, Ting Wang
BACKGROUND: Nicotinic acetylcholine receptors (nAChRs) play an important role in cellular physiology and human nicotine dependence, and are closely associated with many human diseases including cancer. For example, previous studies suggest that nAChRs can re-wire gene regulatory networks in lung cancer cell lines. However, the tissue specificity of nAChRs genes and their regulation remain unexplored. RESULT: In this study, we integrated data from multiple large genomic consortiums, including ENCODE, Roadmap Epigenomics, GTEx, and FANTOM, to define the transcriptomic and epigenomic landscape of all nicotinic receptor genes across many different human tissues and cell types...
June 5, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28579575/prenatal-and-early-postnatal-noael-dose-clothianidin-exposure-leads-to-a-reduction-of-germ-cells-in-juvenile-male-mice
#17
Shogo Yanai, Tetsushi Hirano, Takuya Omotehara, Tadashi Takada, Naoki Yoneda, Naoto Kubota, Anzu Yamamoto, Youhei Mantani, Toshifumi Yokoyama, Hiroshi Kitagawa, Nobuhiko Hoshi
Neonicotinoids are pesticides used worldwide. They bind to insect nicotinic acetylcholine receptors (nAChRs) with high affinity. We previously reported that clothianidin (CTD), one of the latest neonicotinoids, reduced antioxidant expression and induced germ cell death in the adult testis of vertebrates. Here, we investigated the male reproductive toxicity of prenatal and early postnatal exposure to CTD, because it is likely that developmental exposure more severely affects the testis compared to adults due to the absence of the blood-testis barrier...
June 3, 2017: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/28579351/preclinical-abuse-liability-assessment-of-abt-126-an-agonist-at-the-%C3%AE-7-nicotinic-acetylcholine-receptor-nachr
#18
Thomas J Hudzik, Ana M Basso, James J Lynch, William M Bracken, Eric G Mohler, Kathy L Kohlhaas, Hongyu Xu, George Haig, Laura Gault
ABT-126 is a nicotinic acetylcholine receptor (nAChR) agonist that is selective for the α7 subtype of the receptor. nAChRs are thought to play a role in a variety of neurocognitive processes and have been a pharmacologic target for disorders with cognitive impairment, including schizophrenia and Alzheimer's disease. As part of the preclinical safety package for ABT-126, its potential for abuse was assessed. While the involvement of the α4β2 subtype of the nicotinic receptor in the addictive properties of nicotine has been demonstrated, the role of the α7 receptor has been studied much less extensively...
July 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28576119/nicotine-stimulates-collagen-type-i-expression-in-lung-via-%C3%AE-7-nicotinic-acetylcholine-receptors
#19
Glenn W Vicary, Jeffrey D Ritzenthaler, Tanmay S Panchabhai, Edilson Torres-González, Jesse Roman
BACKGROUND: Tobacco-related chronic lung diseases are characterized by alterations in lung architecture leading to decreased lung function. Knowledge of the exact mechanisms involved in tobacco-induced tissue remodeling and inflammation remains incomplete. We hypothesize that nicotine stimulates the expression of extracellular matrix proteins, leading to relative changes in lung matrix composition, which may affect immune cells entering the lung after injury. METHODS: Pulmonary fibroblasts from wildtype and α7 nicotinic acetylcholine receptor knockout (α7KO) mice were exposed to nicotine and examined for collagen type 1 mRNA and protein expression...
June 2, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28554861/galantamine-alleviates-senescence-of-u87-cells-induced-by-beta-amyloid-through-decreasing-ros-production
#20
Yan Zhang, Lingling Zhao, Zhaoxuan Wu, Xinxin Chen, Tong Ma
Galantamine, which is currently used in the treatment of Alzheimer's disease (AD), has been shown to exert a neuroprotective effect against beta-amyloid (Aβ) peptide-induced toxicity, a critical component involved in the pathogenesis of AD. The aim of this study was to examine the effects of galantamine on proliferation, senescence and ROS production in a U87 cell line treated with Aβ. With the use of a Cell Counting Kit-8 and β galactosidase staining assay, we observed that galantamine (0.3μM) pretreatment significantly prevented Aβ1-40-induced cell degradation and senescence...
May 26, 2017: Neuroscience Letters
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