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Patch clamp nAChR

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
Xujiao Zhou, Yun Cheng, Rong Zhang, Gang Li, Boqi Yang, Shenghai Zhang, Jihong Wu
Alpha-7 nicotinic acetylcholine receptor (α7-nAChR) agonists can prevent glutamate-induced excitotoxicity in cultured retinal ganglion cells (RGCs). However, the neuroprotective effects and the mechanism of action of PNU-282987, an α7-nAChR agonist, in a chronic in vivo rat glaucoma model are poorly understood. We found that elevated intraocular pressure (IOP) downregulated retinal α7-nAChR expression. Electroretinography revealed that the amplitude of the photopic negative response (PhNR) decreased in parallel with the loss of RGCs caused by elevated IOP...
May 11, 2017: Scientific Reports
Saurabh Verma, Sudhanva Srinivas Kashyap, Alan Patrick Robertson, Richard John Martin
Many techniques for studying functional genomics of important target sites of anthelmintics have been restricted to Caenorhabditis elegans because they have failed when applied to animal parasites. To overcome these limitations, we have focused our research on the human nematode parasite Brugia malayi, which causes elephantiasis. Here, we combine single-cell PCR, whole muscle cell patch clamp, motility phenotyping (Worminator), and dsRNA for RNAi for functional genomic studies that have revealed, in vivo, four different muscle nAChRs (M-, L-, P-, and N-)...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
Monique J Windley, Irina Vetter, Richard J Lewis, Graham M Nicholson
κ-Hexatoxins (κ-HXTXs) are a family of excitotoxic insect-selective neurotoxins from Australian funnel-web spiders that are lethal to a wide range of insects, but display no toxicity towards vertebrates. The prototypic κ-HXTX-Hv1c selectively blocks native and expressed cockroach large-conductance calcium-activated potassium (BKCa or KCa1.1) channels, but not their mammalian orthologs. Despite this potent and selective action on insect KCa1.1 channels, we found that the classical KCa1.1 blockers paxilline, charybdotoxin and iberiotoxin, which all block insect KCa1...
April 8, 2017: Neuropharmacology
Lucas C Armstrong, Glenn E Kirsch, Nikolai B Fedorov, Caiyun Wu, Yuri A Kuryshev, Abby L Sewell, Zhiqi Liu, Arianne L Motter, Carmine S Leggett, Michael S Orr
Nicotine, the addictive component of tobacco products, is an agonist at nicotinic acetylcholine receptors (nAChRs) in the brain. The subtypes of nAChR are defined by their α- and β-subunit composition. The α6β2β3 nAChR subtype is expressed in terminals of dopaminergic neurons that project to the nucleus accumbens and striatum and modulate dopamine release in brain regions involved in nicotine addiction. Although subtype-dependent selectivity of nicotine is well documented, subtype-selective profiles of other tobacco product constituents are largely unknown and could be essential for understanding the addiction-related neurological effects of tobacco products...
July 2017: SLAS Discovery
Huahua Sun, Yang Liu, Jian Li, Xinzhu Cang, Haibo Bao, Zewen Liu
The american cockroach (Periplaneta americana) dorsal unpaired median (DUM) neurons provide an native tool to analyze the functional and pharmacological properties of ion channels and membrane receptors, such as nicotine acetylcholine receptors (nAChRs). Here the imidacloprid-activated nAChR subtypes were examined in DUM neurons by the patch-clamp technique and the potential subunits involved in important subtypes were analyzed by combining with RNA interference (RNAi) technique. Imidacloprid exerted agonist activities on one subtype in α-Bgt-sensitive nAChRs and another subtype in α-Bgt-resistant nAChRs, in which the α-Bgt-resistant subtype showed much higher sensitivity to imidacloprid than the α-Bgt-sensitive subtype, with the difference close to 200-fold...
February 2017: Insect Biochemistry and Molecular Biology
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...
February 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Arik J Hone, J Michael McIntosh, Lola Rueda-Ruzafa, Juan Passas, Cristina de Castro-Guerín, Jesús Blázquez, Carmen González-Enguita, Almudena Albillos
Varenicline is a nicotinic acetylcholine receptor (nAChR) agonist used to treat nicotine addiction, but a live debate persists concerning its mechanism of action in reducing nicotine consumption. Although initially reported as α4β2 selective, varenicline was subsequently shown to activate other nAChR subtypes implicated in nicotine addiction including α3β4. However, it remains unclear whether activation of α3β4 nAChRs by therapeutically relevant concentrations of varenicline is sufficient to affect the behavior of cells that express this subtype...
January 2017: Journal of Neurochemistry
Glenn E Kirsch, Nikolai B Fedorov, Yuri A Kuryshev, Zhiqi Liu, Lucas C Armstrong, Michael S Orr
The Family Smoking Prevention and Tobacco Control Act of 2009 (Public Law 111-31) gave the US Food and Drug Administration (FDA) the responsibility for regulating tobacco products. Nicotine is the primary addictive component of tobacco and its effects can be modulated by additional ingredients in manufactured products. Nicotine acts by mimicking the neurotransmitter acetylcholine on neuronal nicotinic acetylcholine receptors (nAChRs), which function as ion channels in cholinergic modulation of neurotransmission...
August 2016: Assay and Drug Development Technologies
Marina Cholanian, Gregory L Powell, Richard B Levine, Ralph F Fregosi
Developmental nicotine exposure (DNE) is associated with increased risk of cardiorespiratory, intellectual, and behavioral abnormalities in neonates, and is a risk factor for apnea of prematurity, altered arousal responses and Sudden Infant Death Syndrome. Alterations in nicotinic acetylcholine receptor signaling (nAChRs) after DNE lead to changes in excitatory neurotransmission in neural networks that control breathing, including a heightened excitatory response to AMPA microinjection into the hypoglossal motor nucleus...
January 2017: Experimental Neurology
Silvia Corsini, Maria Tortora, Andrea Nistri
KEY POINTS: Impaired uptake of glutamate builds up the extracellular level of this excitatory transmitter to trigger rhythmic neuronal bursting and delayed cell death in the brainstem motor nucleus hypoglossus. This process is the expression of the excitotoxicity that underlies motoneuron degeneration in diseases such as amyotrophic lateral sclerosis affecting bulbar motoneurons. In a model of motoneuron excitotoxicity produced by pharmacological block of glutamate uptake in vitro, rhythmic bursting is suppressed by activation of neuronal nicotinic receptors with their conventional agonist nicotine...
November 15, 2016: Journal of Physiology
Weston A Nichols, Brandon J Henderson, Christopher B Marotta, Caroline Y Yu, Chris Richards, Dennis A Dougherty, Henry A Lester, Bruce N Cohen
A number of mutations in α4β2-containing (α4β2*) nicotinic acetylcholine (ACh) receptors (nAChRs) are linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), including one in the β2 subunit called β2V287L. Two α4β2* subtypes with different subunit stoichiometries and ACh sensitivities co-exist in the brain, a high-sensitivity subtype with (α4)2(β2)3 subunit stoichiometry and a low-sensitivity subtype with (α4)3(β2)2 stoichiometry. The α5 nicotinic subunit also co-assembles with α4β2 to form a high-sensitivity α5α4β2 nAChR...
2016: PloS One
Mei-Fang Chen, Su-Yu Lai, Po-Cheng Kung, Yo-Cheng Lin, Hui-I Yang, Po-Yi Chen, Ingrid Y Liu, Ahai Chang Lua, Tony Jer-Fu Lee
The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O2 demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp, and calcium imaging...
August 15, 2016: Toxicology and Applied Pharmacology
Mami Noda, A I Kobayashi
Alpha 7 subunits of nicotinic acetylcholine receptors (nAChRs) are expressed in microglia and are involved in the suppression of neuroinflammation. Over the past decade, many reports show beneficial effects of nicotine, though little is known about the mechanism. Here we show that nicotine inhibits lipopolysaccharide (LPS)-induced proton (H(+)) currents and morphological change by using primary cultured microglia. The H(+) channel currents were measured by whole-cell patch clamp method under voltage-clamp condition...
January 2017: Journal of Physiological Sciences: JPS
Camila Carignano, Esteban Pablo Barila, Guillermo Spitzmaul
The neuronal nicotinic acetylcholine receptor α4β2 forms pentameric proteins with two alternate stoichiometries. The high-sensitivity receptor is related to (α4)2(β2)3 stoichiometry while the low-sensitivity receptor to (α4)3(β2)2 stoichiometry. Both subtypes share two binding sites at the α4((+))/β2((-)) interface with high affinity for agonists. (α4)3(β2)2 has an additional binding site at the α4((+))/α4((-)) interface with low affinity for agonists. We investigated activation kinetics of both receptor subtypes by patch-clamp recordings of single-channel activity in the presence of several concentrations of acetylcholine (0...
September 2016: Biochimica et Biophysica Acta
Lei Shen, Wen-yu Cui, Ru-zhu Chen, Hai Wang
AIM: To explore the modulatory effect of desensitized α7-containing nicotinic receptors (α7-nAChRs) on excitatory and inhibitory amino acid receptors in cultured hippocampal neurons and to identify the mechanism underlying this effect. METHODS: Whole-cell patch-clamp recordings were performed on cultured rat hippocampal neurons to measure α7-nAChR currents and to determine the role of desensitized α7-nAChRs on brain amino acid receptor activity. RESULTS: Pulse and perfusion applications of the α7-nAChR agonist choline were applied to induce different types of α7-nAChR desensitization in cultured hippocampal neurons...
March 2016: Acta Pharmacologica Sinica
Kazi T Ahmed, Declan W Ali
Nicotinic acetylcholine receptors (nAChRs) are highly expressed at the vertebrate neuromuscular junction (NMJ) where they are required for muscle activation. Understanding the factors that underlie NMJ development is critical for a full understanding of muscle function. In this study we performed whole cell and outside-out patch clamp recordings, and single-cell RT-qPCR from zebrafish red and white muscle to examine the properties of nAChRs during the first 5 days of development. In red fibers miniature endplate currents (mEPCs) exhibit single exponential time courses at 1...
August 2016: Developmental Neurobiology
Simone Brusco, Paola Ambrosi, Simone Meneghini, Andrea Becchetti
Regulation of the "neuronal" nicotinic acetylcholine receptors (nAChRs) is implicated in both tobacco addiction and smoking-dependent tumor promotion. Some of these effects are caused by the tobacco-derived N-nitrosamines, which are carcinogenic compounds that avidly bind to nAChRs. However, the functional effects of these drugs on specific nAChR subtypes are largely unknown. By using patch-clamp methods, we tested 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) on human α4β2 nAChRs...
2015: Frontiers in Pharmacology
Jessica Oyola-Cintrón, Daniel Caballero-Rivera, Leomar Ballester, Carlos A Baéz-Pagán, Hernán L Martínez, Karla P Vélez-Arroyo, Orestes Quesada, José A Lasalde-Dominicci
Lipid rafts, specialized membrane microdomains in the plasma membrane rich in cholesterol and sphingolipids, are hot spots for a number of important cellular processes. The novel nicotinic acetylcholine receptor (nAChR) mutation αC418W, the first lipid-exposed mutation identified in a patient that causes slow channel congenital myasthenia syndrome was shown to be cholesterol-sensitive and to accumulate in microdomains rich in the membrane raft marker protein caveolin-1. The objective of this study is to gain insight into the mechanism by which lateral segregation into specialized raft membrane microdomains regulates the activable pool of nAChRs...
October 30, 2015: Journal of Biological Chemistry
Arik J Hone, J Michael McIntosh, Layla Azam, Jon Lindstrom, Linda Lucero, Paul Whiteaker, Juan Passas, Jesús Blázquez, Almudena Albillos
Ligands that selectively inhibit human α3β2 and α6β2 nicotinic acetylcholine receptor (nAChRs) and not the closely related α3β4 and α6β4 subtypes are lacking. Current α-conotoxins (α-Ctxs) that discriminate among these nAChR subtypes in rat fail to discriminate among the human receptor homologs. In this study, we describe the development of α-Ctx LvIA(N9R,V10A) that is 3000-fold more potent on oocyte-expressed human α3β2 than α3β4 and 165-fold more potent on human α6/α3β2β3 than α6/α3β4 nAChRs...
November 2015: Molecular Pharmacology
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