购买Nicotinic Acetylcholine Receptor beta兔多克隆抗体(ab66429),Nicotinic Acetylcholine Receptor beta抗体经WB,IHC-Fr验证,可与人样本反应。中国现货速达。
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Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular ...
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TY - JOUR. T1 - Interaction of benzylidene-anabaseine analogues with agonist and allosteric sites on muscle nicotinic acetylcholine receptors. AU - Arias, H. R.. AU - Xing, H.. AU - MacDougall, K.. AU - Blanton, M. P.. AU - Soti, F.. AU - Kern, W. R.. PY - 2009/5/1. Y1 - 2009/5/1. N2 - Background and purpose: Benzylidene-anabaseines (BAs) are partial agonists of the α7 nicotinic acetylcholine receptor (nAChR) but their mechanism(s) of action are unknown. Our study explores several possibilities, including direct interactions of BAs with the nAChR channel. Experimental approach: Functional and radioligand-binding assays were used to examine the interaction of two BA analogues, 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) and Its primary metabolite 3-(4-hydroxy-2-methoxybenzylidene)anabaseine (4OH-DMXBA) with both agonist and non-competitive antagonist (NCA)-bindlng sites on muscle-type nAChRs. Key results: Both BAs non-competitively inhibited ACh activation of human fetal muscle nAChRs and ...
Goat polyclonal Nicotinic Acetylcholine Receptor beta 2 antibody validated for WB and tested in Human. Immunogen corresponding to synthetic peptide
Nicotinic Acetylcholine Receptor beta小鼠单克隆抗体[B3](ab11150)可与人样本反应并经WB, IP, IHC, Flow Cyt实验严格验证,被5篇文献引用。
BioAssay record AID 145983 submitted by ChEMBL: Binding affinity towards rat nicotinic acetylcholine receptor alpha2-beta2 expressed in HEK293 cells using [3H]EB as radioligand.
Elliott, K.J.; Ellis, S.B.; Berckhan, K.J.; Urrutia, A.; Chavez-Noriega, L.E.; Johnson, E.C.; Veliçelebi, G.; Harpold, M.M., 1996: Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits
Molecular and cell biological characterisation of neuronal nicotinic acetylcholine receptors (nAChRs) provides an insight into their functional roles and potential as therapeutic targets for neurological disorders. Nicotinic receptors are oligomeric ligand-gated ion channels, comprising five subunits. Twelve vertebrate neuronal nAChR subunits (2-10 and 2-4) have been cloned to date, with considerable diversity observed in nAChR subunit composition. Heterologous expression of cloned subunits is a powerful method for investigating ion channel receptor pharmacology and subunit composition, but achieving efficient expression of some nAChRs in cultured cell lines has proved difficult. In this study, chimeras containing the N-terminal domain of the nAChR subunits, fused to the C-terminal region of the 5-hydroxtryptamine type 3 receptor subunit, 5HT3A, were constructed to overcome some of the challenges of recombinant nAChR expression. When combinations of wild-type and chimeric subunits were expressed ...
Nicotine is a chemical with multiple biological and neurological actions. It is a natural alkaloid that mimics the effects of acetylcholine as a neurotransmitter. Nicotinic acetylcholine receptors are cholinergic receptors that activate ligand-gated ion channels in the plasma membranes of certain neurons and muscle cells. These ion channels are opened by the binding of nicotine. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors, being found throughout the nervous system and in the neuromuscular junctions of somatic muscles. When the channel opens, positively-charged sodium ions enter the cell and positively-charged potassium ions exit for a net positive increase inside the cell. Research suggests that nicotinic acetylcholine receptors may have a role in cognitive performance, as well as affecting mood, reducing pain sensitivity, and enhancing the release of other neurotransmitters. Sigma-Aldrich offers antibodies that have agonist and antagonist effects on nicotinic
It is well established that nicotinic receptors in the mammalian striatum are involved in modulation of the release of several neurotransmitters, including dopamine. In addition, nicotinic receptors with high affinity for agonists have generally been found to be reduced in the striatum in Parkinsons disease. In the present study antibodies have been used to examine which subunits contribute to the striatal nicotinic receptor loss in Parkinsons disease, and whether the reduction in [(3)H]nicotine binding correlates with synaptic loss. Autopsy tissue from the putamen of 12 Parkinsons disease cases and 12 age-matched control subjects was analysed by immunoblotting using antibodies against recombinant peptides specific for alpha3, alpha4, alpha7, beta2 and beta4 nicotinic acetylcholine receptor (nAChR) subunits and the synaptic marker synaptophysin, in conjunction with assessment of [(3)H]nicotine binding by autoradiography. The data indicate that there is no loss of alpha3, alpha4, alpha7 and beta2
Neuronal nicotinic acetylcholine receptors (nAChRs) are excitatory ligand‐gated ion channels that perform important roles throughout the nervous systems of both vertebrate and invertebrate organisms. Impairments to human nAChRs and cholinergic transmission are thought to underlie the pathophysiologies of several neurological and psychological diseases including schizophrenia, Alzheimers disease, Parkinsons disease and certain forms of epilepsy. They are also the receptors that mediate the effects of tobacco smoking and contribute to the physiological and psychological changes associated with nicotine addiction. The aim of this thesis is to further our understanding of neuronal nAChRs from a pharmacological and molecular viewpoint. Research described in this thesis focuses on numerous aspects of neuronal nAChRs; allosteric modulators, insect nAChRs and chaperone proteins. Allosteric modulators of nAChRs are ligands that alter the receptors responsiveness to agonists via sites that are ...
Acetylcholine (ACh) is an important neurotransmitter in the mammalian brain; it is implicated in arousal, learning, and other cognitive functions. Recent studies indicate that nicotinic receptors contribute to these cholinergic effects, in addition to the established role of muscarinic receptors. In the hippocampus, where cholinergic involvement in learning and memory is particularly well documented, 7 nicotinic acetylcholine receptor subunits (7 nAChRs) are highly expressed, but their precise ultrastructural localization has not been determined. Here, we describe the results of immunogold labeling of serial ultrathin sections through stratum radiatum of area CA1 in the rat. Using both anti-7 nAChR immunolabeling and -bungarotoxin binding, we find that 7 nAChRs are present at nearly all synapses in CA1 stratum radiatum, with immunolabeling present at both presynaptic and postsynaptic elements. Morphological considerations and double immunolabeling indicate that GABAergic as well as glutamatergic ...
We and others have shown that one of the mechanisms of growth regulation of small cell lung cancer cell lines and cultured pulmonary neuroendocrine cells is by the binding of agonists to the α7 neuronal nicotinic acetylcholine receptor. In addition, we have shown that the nicotine-derived carcinogenic nitrosamine, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a high affinity agonist for the α7 nicotinic acetylcholine receptor. In the present study, our goal was to determine the extent of α7 mRNA and protein expression in the human lung. Experiments were done using reverse transcription polymerase chain reaction (RT-PCR), a nuclease protection assay and western blotting using membrane proteins. We detected mRNA for the neuronal nicotinic acetylcholine receptor α7 receptor in seven small cell lung cancer (SCLC) cell lines, in two pulmonary adenocarcinoma cell lines, in cultured normal human small airway epithelial cells (SAEC), one carcinoid cell line, three squamous cell lines and tissue
TY - JOUR. T1 - Adult forms of nicotinic acetylcholine receptors are expressed in the absence of nerve during differentiation of a mouse skeletal muscle cell line. AU - Shepherd, Dawn. AU - Brehm, Paul. PY - 1994. Y1 - 1994. N2 - Changes in the functional properties of acetylcholine receptor (AchR) channels were followed in the C2 muscle cell line over the period of 1 to 17 days following myotube formation. Up to 1 week after myotube formation, the predominant class of channel exhibited low (45 pS) conductance and long mean channel open time (14 msec), characteristic of the major type of AchR in embryonic skeletal muscle. Three additional Ach-activated currents with conductances lower than 45 pS and long channel open times were also observed. Seven to 10 days following myotube formation, channels of 45 pS and 65 pS and short (2-6 msec) mean open duration were observed, characteristic of receptor channels in adult muscle. Increases in ε subunit mRNA levels preceded the functional expression of ...
Citation: Green, B.T., Welch, K.D., Cook, D., Gardner, D.R. 2011. Potentiation of the actions of acetylcholine, epibatidine, and nicotine by methyllycaconitine at fetal muscle-type nicotinic acetylcholine receptors. European Journal of Pharmacology. 662(1-3):15-21. Interpretive Summary: Toxic alkaloids from larkspur species cause muscle weakness in cattle. One alkaloid in particular, MLA, is found in high concentrations in toxic larkspur. This alkaloid is a potent and selective blocker of neuronal nicotinic acetylcholine receptors. This study characterized the affects of the blocker MLA on the actions of three nicotinic acetylcholine receptor agonists. These effects were assessed by measuring changes in membrane potential sensing dye responses of TE-671 cells. Changes in cell membrane potential from the addition of agonists were measured as changes in fluorescence of a membrane potential-sensitive dye. MLA alone was without effect. MLA at low concentrations potentiated the response of TE-671 ...
The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant nAChR type in the brain, and this receptor type exists in alternate (α4β2)2α4 and (α4β2)2β2 forms, which are activated by agonists with strikingly differing efficacies. Recent breakthroughs have identified an additional operational agonist binding site in the (α4β2)2α4 nAChR that is responsible for the signature sensitivity of this receptor to activation by agonists, yet the structural mechanisms determining agonist efficacy at this receptor type are not yet fully understood. In this study, we characterized the ligand selectivity of the individual agonist sites of the (α4β2)2α4 nAChR to determine whether differences in agonist selectivity influence agonist efficacy. Applying the substituted cysteine accessibility method to individual agonist sites in concatenated (α4β2)2α4 receptors, we determined the agonist selectivity of the agonist sites of the (α4β2)2α4 receptor. We show that (a) accessibility of substituted
TY - JOUR. T1 - Luminal and non-luminal non-competitive inhibitor binding sites on the nicotinic acetylcholine receptor (Review). AU - Arias, Hugo R.. PY - 1996/1/1. Y1 - 1996/1/1. N2 - The nicotinic acetylcholine receptor presents two very well differentiated domains for ligand binding that account for different cholinergic properties. In the hydrophilic extracellular region of the a subunit exist the binding sites for agonists such as the neurotransmitter acetylcholine, which upon binding trigger the channel opening, and for competitive antagonists such as d-tubocurarine, which compete for the former inhibiting its pharmacological action. For non-competitive inhibitors, a population of low-affinity binding sites have been found at the lipid-protein interface of the nicotinic acetylcholine receptor. In addition, at the M2 transmembrane domain, several high-affinity binding sites have been found for non-competitive inhibitors such as chlorpromazine, triphenylmethylphosphonium, the local ...
RIC-3 (resistant to inhibitor of cholinesterase) is a transmembrane protein, found in invertebrates and vertebrates, that modulates the surface expression of a variety of nicotinic acetylcholine receptors (nAChRs) in neurons and other cells. To understand its mechanism of action, we have investigated the cellular location, transmembrane topology and roles of the functional domains of RIC-3 in facilitating α7 assembly and surface expression in cultured mammalian cells. We show that the mouse protein is targeted to the endoplasmic reticulum (ER) by the first 31 amino acids which act as a cleavable signal sequence. The mature protein is a single-pass type I transmembrane protein whose N-terminus resides in the lumen of the ER with the coiled-coil domain in the cytoplasm. Functional analysis shows that facilitation of surface expression of α7 in mammalian cells is reduced in mutants lacking the signal peptide, the lumenal segment and the coiled-coil domain, but not in those lacking the long ...
Our data illustrate that the α10 −/− phenotype is distinct from that observed in the α9−/− mouse line in terms of hair cell physiological function and synaptic structure. In addition, our data demonstrate that the residual functional α9 nAChRs expressed in α10 −/− mice are insufficient to drive normal OC efferent function. Thus, our data definitively establish the requirement for α10 subunits in forming biologically relevant hair cell nAChRs.. Homomeric α9 nAChRs reconstituted in Xenopus oocytes produce small ACh-evoked currents (25). The presence of small ACh-evoked currents in some α10 −/− OHCs suggests the continued expression of functional α9 receptors that likely consist of homomeric subunits. Lack of nicotine-induced activation in OHCs that are otherwise ACh-responsive is consistent with the presence of α9 homomeric receptors. Moreover, the fact that OHCs from α9−/− mice do not present ACh-evoked currents rules out the possibility that in the absence of ...
This study compares the lipid composition, including individual phospholipid molecular species of solubilized nAChR detergent complexes (nAChR-DCs) with those of the bulk lipids from their source, Torpedo californica (Tc) electric tissue. This lipidomic analysis revealed seventy-seven (77) phospholipid species in the Tc tissue. Analysis of affinity-purified nAChR-DCs prepared with C-12 to C-16 phospholipid analog detergents alkylphosphocholine (FC) and lysofoscholine (LFC) demonstrated that nAChRDCs prepared with FC12, LFC14, and LFC16 contained ,60 phospholipids/nAChR, which was more than twice of those prepared with FC14, FC16, and LFC12. Significantly, all the nAChR-DCs lacked ethanolamine and anionic phospholipids, contained only four cholesterol molecules, and a limited number of phospholipid molecular species per nAChR. Upon incorporation into oocytes, FC12 produce significant functionality, whereas LFC14 and LFC16 nAChR-DCs displayed an increased functionality as compared to the crude Tc ...
Description: Gamma-Aminobutyric Acid Receptor Subunit Alpha 5 (GABA(A) Receptor Subunit Alpha 5 or GABRA5) - Gamma-aminobutyric acid A receptor, alpha 5 or
Title: Cognitive Improvement by Activation of α7 Nicotinic Acetylcholine Receptors: From Animal Models to Human Pathophysiology. VOLUME: 16 ISSUE: 3. Author(s):Morten S. Thomsen, Henrik H. Hansen, Mikkelsen B. Timmerman and Jens D. Mikkelsen. Affiliation:Neurobiology Research Unit, Copenhagen University Hospital, Juliane Maries Vej 24, building 9201, DK-2100 Copenhagen, Denmark.. Keywords:Nicotine, Alzheimers disease, schizophrenia, attention, working memory, prefrontal cortex, hippocampus, acetylcholine. Abstract: Agonists and positive allosteric modulators of the α7 nicotinic acetylcholine receptor (nAChR) are currently being developed for the treatment of cognitive disturbances in patients with schizophrenia or Alzheimers disease. This review describes the neurobiological properties of the α7 nAChR and the cognitive effects of α7 nAChR activation, focusing on the translational aspects in the development of these drugs. The functional properties and anatomical localization of the α7 ...
Urokinase plasminogen activator (uPA) contributes to atherosclerosis, restenosis and vascular remodeling. We have recently identified nAChRα1 as a functional cell receptor for uPA in addition to its classic receptor, uPAR. Here, we test the hypothesis that nAChRα1 plays a role in the pathogenesis of atherosclerosis. C57BL/6J ApoE−/− mice (male) were initially fed a Western diet for 8 wks. Plasmid DNA encoding scramble RNA (pScr) or siRNA (pSir2) for nAChRα1 was then injected into the mice (n=15) using an aortic hydrodynamic gene transfer protocol. Three mice from each group were sacrificed 7 days after DNA injection to confirm the nAChRα1 gene silencing. The rest of the mice continued on the Western diet for an additional 16 wks. Aortas were harvested for paraffin-embedding (aorta root), protein (ascending aorta and aortic arch) and RNA (descending aorta) (n=8). Whole aortas were isolated for oil red staining in 4 mice of each group. The nAChRα1 was highly up-regulated in aortic ...
Ethylbenzene and para-xylene (p-xylene), but not the chemically closely related organic solvents ortho-xylene (o-xylene) and meta-xylene (m-xylene), are known to cause ototoxicity and irreversible hearing loss, though the underlying mechanisms are still unknown. In this study, effects of ethylbenzene and of p-, o-, and m-xylene on human heteromeric α9α10 nicotinic ... read more acetylcholine receptors (nAChRs) expressed in Xenopus oocytes were investigated using the two-electrode voltage clamp technique. ACh dose-dependently evoked an α9α10 nAChR-mediated ion current with an EC50 of 137 μM. When ACh is applied at a low concentration (10 μM), the nAChR-mediated ion current is inhibited by a low concentration (10 μM) of ethylbenzene and p-xylene, but not by the same concentration of the non-ototoxic solvents. At a high solvent concentration (300 μM), all solvents cause inhibition of the ion currents evoked by 10 μM ACh. Ion currents evoked by a near maximum-effective concentration ACh (1 ...
mRNAs for the neuronal nicotinic acetylcholine receptor (nAChR) α6 and β3 subunits are abundantly expressed and colocalized in dopaminergic cells of the substantia nigra and ventral tegmental area. Studies using subunit-null mutant mice have shown that α6- or β3-dependent nAChRs bind α-conotoxin MII (α-CtxMII) with high affinity and modulate striatal dopamine release. This study explores the effects of β3 subunit-null mutation on striatal and midbrain nAChR expression, composition, and pharmacology. Ligand binding and immunoprecipitation experiments using subunit-specific antibodies indicated that β3-null mutation selectively reduced striatal α6* nAChR expression by 76% versus β3+/+ control. Parallel experiments showed a smaller reduction in both midbrain α3* and α6* nAChRs (34 and 42% versus β3+/+ control, respectively). Sedimentation coefficient determinations indicated that residual α6* nAChRs in β3-/- striatum were pentameric, like their wild-type counterparts. ...
TY - JOUR. T1 - Central nicotinic acetylcholine receptor involved in Ca 2+- calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects. AU - Cheng, Pei Wen. AU - Lu, Pei Jung. AU - Chen, Siang Ru. AU - Ho, Wen Yu. AU - Cheng, Wen Han. AU - Hong, Ling Zong. AU - Yeh, Tung Chen. AU - Sun, Gwo Ching. AU - Wang, Ling Lin. AU - Hsiao, Michael. AU - Tseng, Ching Jiunn. PY - 2011/7/1. Y1 - 2011/7/1. N2 - BACKGROUND AND PURPOSE Recent evidence has suggested that nicotine decreases blood pressure (BP) and heart rate (HR) in the nucleus tractus solitarii (NTS), indicating that nicotinic acetylcholine receptors (nAChRs) play an important role in BP control in the NTS. However, the signalling mechanisms involved in nAChR-mediated depressor effects in the NTS are unclear. Hence, the aim of this study was to investigate these signalling mechanisms. EXPERIMENTAL APPROACH Depressor responses to nicotine microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and ...
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Kullberg, R. W. and Zheng, Y. C. and Todt, W. et al. (1994) Structure and expression of the nicotinic acetylcholine receptor beta subunit of Xenopus laevis. Receptors & Channels, 2 (1). pp. 23-31. ISSN 1060-6823. https://resolver.caltech.edu/CaltechAUTHORS:20151231-001701500 ...
Purpose : Presynaptic modulation of γ-aminobutyric acid (GABA) release by an alpha7 nicotinic acetylcholine receptor (α7-nAChR) agonist promotes retinal ganglion cell (RGC) survival and function, as suggested by a previous study on a chronic glaucomatous model from our laboratory. However, the role of excitatory and inhibitory amino acid receptors and their interaction with α7-nAChR in physiological and glaucomatous events remains unknown. Methods : Using patch clamp techniques, the GABA-elicited membrane current and miniature excitatory postsynaptic currents (mEPSCS) of RGCs and the NMDA-gated current (INMDA) were detected in rat retinal slices. The expression of the GABAA receptor and NMDA receptors (NMDAR) subunit NR1, NR2A and NR2B in retinas were detected using western blotting and immunostaining. Results : Whole-cell patch-clamp recordings from RGCs revealed profound changes in the GABAA receptor and NMDAR properties under glaucoma conditions. The α7-nAChR specific agonist PNU-282987 ...
Our aim was to investigate the role of nicotinic acetylcholine receptors (nAChRs) in in-vitro osteoclastogenesis and in in-vivo bone homeostasis. The presence of nAChR subunits as well as the in-vitro effects of nAChR agonists were investigated by ex vivo osteoclastogenesis assays, real-time polymerase chain reaction, Western blot and flow cytometry in murine bone marrow-derived macrophages differentiated in the presence of recombinant receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). The bone phenotype of mice lacking various nAChR subunits was investigated by peripheral quantitative computed tomography and histomorphometric analysis. Oscillations in the intracellular calcium concentration were detected by measuring the Fura-2 fluorescence intensity. We could demonstrate the presence of several nAChR subunits in bone marrow-derived macrophages stimulated with RANKL and M-CSF, and showed that they are capable of producing acetylcholine. nAChR
In the February 2009 issue of the Journal of General Physiology, we published a paper in which we presented (among several other results) a novel, single-channel-based approach to estimating the fractional Ca2+ currents through neurotransmitter-gated ion channels (Elenes et al., 2009). We applied the method to a variety of mutant and wild-type muscle nicotinic acetylcholine receptors (AChRs) and to the NMDA receptor composed of NR1 and NR2A subunits, all heterologously expressed in HEK-293 cells. Our goal was to estimate the impact of a panel of naturally occurring mutations on the Ca2+-permeation properties of the AChR.. Our methodology is based on the observation that (in the presence of saturating concentrations of, say, Na+ in the pipette solution of cell-attached patches) increasing concentrations of Ca2+ in the pipette reduce the inward single-channel conductance, eventually reaching a nonzero value that coincides with the single-channel conductance measured in the presence of Ca2+ alone ...
(E)-5-(Pyrimidin-5-yl)-1,2,3,4,7,8-hexahydroazocine (TC299423) is a novel agonist for nicotinic acetylcholine receptors (nAChRs). We examined its efficacy, affinity, and potency for α6β2* (α6β2-containing), α4β2*, and α3β4* nAChRs, using [125I]-epibatidine binding, whole-cell patch-clamp recordings, and synaptosomal 86Rb+ efflux, [3H]-dopamine release, and [3H]-acetylcholine release. TC299423 displayed an EC50 of 30 - 60 nM for α6β2* nAChRs in patch-clamp recordings and [3H]-dopamine release assays. Its potency for α6β2* in these assays was 2.5-fold greater than that for α4β2*, and much greater than that for α3β4*-mediated [3H]-acetylcholine release. We observed no major off-target binding on 70 diverse molecular targets. TC299423 was bioavailable after intraperitoneal or oral administration. Locomotor assays, measured with gain-of-function mutant α6 (α6L9ʹS) nAChR mice, show that TC299423 elicits α6β2* nAChR-mediated responses at low doses. Conditioned place preference (CPP)
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Genetic mutations responsible for CMSs have been identified in relation to proteins in the presynaptic, synaptic and postsynaptic compartments of the neuromuscular endplate. As expected, the frequency of particular gene mutations varies within different ethnic groups, but in most populations the most common form of CMS is due to a deficiency of acetylcholine receptors on the postsynaptic membrane [3]. These can result from recessive missense, nonsense, frameshift or splice site and promoter region mutations in any of the genes encoding the acetylcholine receptor subunits. However, a high frequency of mutations in the acetylcholine receptor ε subunit (CHRNE) compared with other subunits has been recognised and attributed to the phenotypic rescue by maintained low level expression of the foetal γ subunit that substitutes for the defective ε subunit, but cannot compensate for the other muscle acetylcholine receptor subunits. Our patient was diagnosed with c.183_187dupCTCAC within CHRNE, which is ...
The first recordings from individual ion channels were achieved using the patch-clamp to measure currents through muscle nicotinic acetylcholine receptor/channels (Neher and Sakmann 1976); a technique that subsequently revolutionized studies of channel function and biophysics (Hamill et al., 1981; Hille 2001). Here, we demonstrate the use of optical techniques to obtain analogous physiological information from these same channels, by imaging single-channel Ca2+ flux (SCCaFTs) as a reporter of channel gating. One major advantage over electrophysiological recording is that optical single-channel imaging is massively parallel, providing simultaneous readout from hundreds of channels (Fig. 3). This enormously enhanced dataset should facilitate detailed statistical analysis of Markovian channel behavior. For example, we had shown that N-type channels within the same optical field display divergent open probabilities, with individual channels displaying transitions between low and high frequency ...
Published: 01/19/2018 Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) have potential therapeutic application in neuropathologies associated with decrease in function or loss of nAChRs. In this study, we characterize the pharmacological interactions of the nAChRs PAM, LY2087101, with the α4β2 nAChR using mutational and computational analyses. LY2087101 potentiated ACh-induced currents of low-sensitivity (α4)3(β2)2 and high-sensitivity (α4)2(β2)3 nAChRs with similar potencies albeit to a different maximum potentiation (potentiation I max = ~840 and 450%, respectively). Amino acid substitutions within the α4 subunit transmembrane domain [e.g. α4Leu256 and α4Leu260 within the transmembrane helix 1 (TM1); α4Phe316 within the TM3; and α4Gly613 within TM4] significantly reduced LY2087101 potentiation of (α4)3(β2)2 nAChR. The locations of these amino acid residues and LY2087101 computational docking analyses identify two LY2087101 binding sites: an ...
In this study, we uncovered a new mechanism that inactivates nAChRs on neurons. We show that relatively mild shifts in the intracellular thiol/disulfide redox state toward more oxidative conditions induce a rundown of ACh-evoked currents. Once the ACh-evoked currents run down, they do not recover for at least 1 h; it is as if the receptors become trapped in a long-lasting inactivated state. This ROS-induced rundown of ACh-evoked currents is specific to neuronal nAChRs, because elevating ROS had no detectable effect on muscle nAChRs.. In previous work (De Koninck and Cooper, 1995), we measured gene expression of sympathetic neurons developing in culture. We found that these neurons express five nicotinic receptor transcripts: mRNA for α3 and β4 are the most abundant and increase over the first week in culture; mRNA for β2 and α5 are severalfold lower and remain constant, whereas mRNA for α7 is initially high but falls rapidly within 1-2 d in culture and remains low. Although there are no ...
The a4ß2 subtype of the nicotinic acetylcholine receptor (nAChR) has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of a4ß2 agonists is lacking. Using binding experiments, electrophysiology and X-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at a4ß2 and the acetylcholine binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for a4ß2 receptors. Crystal structures of five agonists with efficacies at a4ß2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong inter-subunit bridge linking ...
We have investigated the topology of the alpha and delta subunits of the nicotinic acetylcholine receptor (AChR) from mammalian muscle synthesized in an in vitro translation system supplemented with dog pancreatic microsomes. Fusion proteins were expressed in which a carboxy-terminal fragment of bovine prolactin was attached downstream of each of the major putative transmembrane domains, M1-M4 and MA, in the AChR subunits. The orientation of the prolactin domain relative to the microsomal membrane was then determined for each protein by a proteolysis protection assay. Since the prolactin domain contains no information which either directs or prevents its translocation, its transmembrane orientation depends solely on sequences within the AChR subunit portion of the fusion protein. When subunit-prolactin fusion proteins with the prolactin domain fused after either M2 or M4 were tested, prolactin-immunoreactive peptides that were larger than the prolactin domain itself were recovered. No ...
Innovative strategies to reduce adult smoking prevalence include using genetic information to motivate cessation and, ultimately, to tailor cessation pharmacotherapy. Success of these interventions depends, in part, on smokers interest and participation in genetic testing related to cessation and their understanding and use of the results (i.e., their genetic literacy). The recent availability of genetic risk testing for a nicotinic acetylcholine receptor gene (CHRNA3) variant (rs105173) associated with nicotine dependence makes it highly feasible to investigate smokers interest in and use of genetic information about nicotine dependence. Therefore, the primary purpose of this study is to determine the impact of an intervention that provides smokers with an educational session about genetic contributions to smoking and nicotine dependence plus their genotype results for rs1051730 on smoking cessation outcomes compared to those who receive only the educational session. Secondary purposes are to ...
Nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of ligand-gated ion channels and are distributed widely in the human and nonhuman brain. Several nAChRs have been identified and characterized pharmacologically and have distinct patterns of distribution in the brain. The nicotine alpha 4 beta 2 receptor subtypes are thought to play a role in various diseases, including various brain disorders (e.g., Alzheimers disease), behavioral disorders (e.g., schizophrenia or substance abuse), various neoplasms (e.g., lung cancer), and other diseases, and may also be involved in the addiction to nicotine in chronic tobacco users (tobacco use may increase the number of the alpha 4 beta 2 receptor sites). The development of noninvasive imaging methods using PET and SPECT of the alpha 4 beta 2 receptor system has gained significant interest. Therefore, and not surprisingly, the development of noninvasive imaging methods using PET and SPECT of the alpha 4 beta 2 receptor system has gained
Signal transduction, the process by which an extracellular signal is translated into an intracellular message, underlies all brain function. This thesis examines the role of protein phosphorylation in mediating three different molecular mechanisms by which neurotransmitter receptors transduce their signals: chemically-gated ion channels, receptor-linked ion channels and receptor-linked ion pumps. The nicotinic acetylcholine receptor, a neurotransmitter-gated ion channel, is phosphorylated by a protein tyrosine kinase in postsynaptic membranes in vitro and in vivo. Purified nicotinic receptor molecules from Torpedo electroplaques can be phosphorylated to known stoichiometries and reconstituted into lipid vesicles. Tyrosine phosphorylation increases the rate of the rapid phase of desensitization of the receptor as measured by single channel recording but does not alter other channel properties. These data provide direct evidence for the regulation of ion channel properties by tyrosine phosphorylation and
Background: The frequent co-abuse of alcohol and tobacco may suggest that they share some common neurological mechanisms. For example, nicotine acts on Nicotinic acetylcholine receptors (nAChRs) in the brain to release dopamine to sustain addiction. Might nAChRs be entwined with alcohol? Objectives: This review summarizes recent studies on the relationship between alcohol and nAChRs, including the role of nAChRs in molecular biological studies, genetic studies and pharmacological studies on alcohol, which indicate that nAChRs have been potently modulated by alcohol. Methods: We performed a cross-referenced literature search on biological, genetic and pharmacological studies of alcohol and nAChRs. Results: Molecular biological and genetic studies indicated that nAChR (genes) may be important in mediating alcohol intake, but we still lack substantial evidence about how it works. Pharmacological studies proved the correlation between nAChRs and alcohol intake, and the association between nicotine and
The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012 ...
5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with 125I and123I. Here we present the results of experiments characterizing this radioiodinated ligand in vitro. The affinity of 5-[125I]iodo-A-85380 for α4β2 nAChRs in rat and human brain is defined by K d values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the α4β2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing α3 and β4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at α7 and muscle-type nAChRs, respectively. Moreover, unlike epibatidine and cytisine, 5-[125I]iodo-A-85380 shows no binding in any brain regions in mice homozygous for a mutation in the β2 subunit of nAChRs. Binding of 5-[125I]iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate ...
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found in the central and peripheral nervous systems. They regulate neurotransmitter release throughout the CNS and facilitate fast synaptic transmission. nAChRs have been implicated in autism, depression, schizophrenia, and nicotine addiction, although not many medications targeting the cholinergic system are available. Positive allosteric modulation is a developing method of pharmacological treatment. Des-formyflustrabromine (dFBr), is a positive allosteric modulator (PAM) of α4β2 nicotinic acetylcholine receptors. Galantamine is both and acetylcholinesterase inhibitor (AChEI) and a PAM that is used in the treatment of Alzheimers disease (AD).. Using two-electrode voltage clamp electrophysiology (TEVC), we investigated the selectivity of dFBr with a series of heteromeric nicotinc receptors. We found that dFBr does not potentiate α3β4, α3β2, or α4β4 receptors. In addition, our results indicate that both α4 and β2 ...
Background: Tamoxifen (TAM) has been the mainstay of endocrine therapy for estrogen receptor-positive (ER+) breast cancer. However, approximately 40% of breast cancer patients eventually acquire TAM resistance. Thus, it is necessary to develop effective methods for enhancing the efficacy of TAM in breast cancer treatment. Preliminary results: Long-term smoking affects of efficacy of breast cancer therapy. Our preliminary results showed that α9-nicotinic acetylcholine receptor (nAchR) mRNA levels were dramatically increased in surgically dissected (Figs. 1-3, , 80-fold, n = 276) and laser capture microdissected (Figure 4, ,80-fold, n = 20) cell clusters isolated from breast tumor tissues compared to normal cells. We found that α9-nAchR was up-regulated by ERα and NFκB under nicotine stimulation in human breast cancer cells (Figs. 5-6). Human neuroendocrine neuron-specific enolase (ENO) can be used as a marker in in vitro screens to identify novel anti-cancer agents. Our results demonstrated ...