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Cys loop receptor

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https://www.readbyqxmd.com/read/29120166/aromatic-residues-in-the-fourth-transmembrane-spanning-helix-m4-are-important-for-gaba%C3%AF-receptor-function
#1
James Cory-Wright, Mona Alqazzaz, Francesca Wroe, Jenny Jeffreys, Lu Zhou, Sarah C R Lummis
GABAρ receptors are a subfamily of the GABAA receptor family of pentameric ligand-gated ion channels (pLGICs). Each of the five subunits has four transmembrane α-helices (M1-M4), with M4 most distant from the central pore. Aromatic residues in this M4 helix are important for receptor assembly in pLGICs and also may interact with adjacent lipids and/or residues in neighboring α-helices and the extracellular domain to modify or enable channel gating. This study examines the role of M4 receptor aromatic residues in the GABAρ receptor transmembrane domain using site-directed mutagenesis and subsequent expression in HEK293 cells, probing functional parameters using a fluorescent membrane-potential-sensitive dye...
November 9, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29063617/ivermectin-and-its-target-molecules-shared-and-unique-modulation-mechanisms-of-ion-channels-and-receptors-by-ivermectin
#2
I-Shan Chen, Yoshihiro Kubo
Ivermectin (IVM) is an antiparasitic drug that is used worldwide and rescues hundreds of millions of people from onchocerciasis and lymphatic filariasis. It was discovered by Satoshi Ōmura and William C. Campbell, to whom the 2015 Nobel Prize in Physiology or Medicine was awarded. It kills parasites by activating glutamate-gated Cl(-) channels, and it also targets several ligand-gated ion channels and receptors, including Cys-loop receptors, P2X4 receptors and fernesoid X receptors. Recently, we found that IVM also activates a novel target, the G-protein-gated inwardly rectifying K(+) channel, and also identified the structural determinant for the activation...
October 23, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29062270/the-glyr-extracellular-%C3%AE-8-%C3%AE-9-loop-a-functional-determinant-of-agonist-potency
#3
Dieter Janzen, Natascha Schaefer, Carolyn Delto, Hermann Schindelin, Carmen Villmann
Ligand-binding of Cys-loop receptors results in rearrangements of extracellular loop structures which are further translated into the tilting of membrane spanning helices, and finally opening of the ion channels. The cryo-EM structure of the homopentameric α1 glycine receptor (GlyR) demonstrated an involvement of the extracellular β8-β9 loop in the transition from ligand-bound receptors to the open channel state. Recently, we identified a functional role of the β8-β9 loop in a novel startle disease mouse model shaky...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28955208/nicotinic-acetylcholine-receptor-%C3%AE-9-and-%C3%AE-10-subunits-are-expressed-in-the-brain-of-mice
#4
Olena Lykhmus, Larysa P Voytenko, Katrin S Lips, Ivonne Bergen, Gabriela Krasteva-Christ, Douglas E Vetter, Wolfgang Kummer, Maryna Skok
The α9 and α10 nicotinic acetylcholine receptor (nAChR) subunits are likely to be the evolutionary precursors to the entire cys-loop superfamily of ligand-gated ion channels, which includes acetylcholine, GABA, glycine and serotonin ionotropic receptors. nAChRs containing α9 and α10 subunits are found in the inner ear, dorsal root ganglia and many non-excitable tissues, but their expression in the central nervous system has not been definitely demonstrated. Here we show the presence of both α9 and α10 nAChR subunits in the mouse brain by RT-PCR and immunochemical approaches with a range of nAChR subunit-selective antibodies, which selectivity was demonstrated in the brain preparations of α7-/-, α9-/- and α10-/- mice...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28901280/neuronal-and-extraneuronal-nicotinic-acetylcholine-receptors
#5
Michele Zoli, Susanna Pucci, Antonietta Vilella, Cecilia Gotti
Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a super-family of Cys-loop ligand-gated ion channels that respond to endogenous acetylcholine (ACh) or other cholinergic ligands. These receptors are also the targets of drugs such as nicotine (the main addictive agent delivered by cigarette smoke) and are involved in a variety of physiological and pathophysiological processes. Numerous studies have shown that the expression and/or function of nAChRs is compromised in many neurological and psychiatric diseases...
September 11, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28899696/serotonin-2a-receptor-disulfide-bridge-integrity-is-crucial-for-ligand-binding-to-different-signalling-states-but-not-for-its-homodimerization
#6
Alba Iglesias, Marta Cimadevila, Rocío Ailim de la Fuente, María Martí-Solano, María Isabel Cadavid, Marián Castro, Jana Selent, María Isabel Loza, José Brea
The serotonin 2A (5-HT2A) receptor is a G-protein coupled receptor (GPCR) with a conserved disulfide bridge formed by Cys(148) (transmembrane helix 3, TM3) and Cys(227) (extracellular loop 2, ECL-2). We hypothesized that disulfide bridges may determine serotonin 5-HT2A receptor functions such as receptor activation, functional selectivity and ligand recognition. We used the reducing agent dithiothreitol (DTT) to determine how the reduction of disulfide bridges affects radioligand binding, second messenger mobilization and receptor dimerization...
November 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28838689/efficient-synthesis-of-the-gabaa-receptor-agonist-trans-4-aminocrotonic-acid-taca
#7
Sean G Forrester, Joshua Foster, Sebastien Robert, Lidya Salim, Jean-Paul Desaulniers
Investigations into the pharmacology of different types of cys-loop GABA receptor have relied for years on the chemical modification of GABA-like compounds. The GABA metabolite GABOB is an attractive molecule to modify due to its convenient chemical structure. In the process of developing new GABA-mimic compounds from GABOB as a starting compound three small molecule GABA derivatives were synthesized using a variety of chemical transformations. Amongst these, a new and reliable method to synthesize TACA (trans-4-aminocrotonic acid) is reported...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28837848/interaction-of-the-red-pigment-concentrating-hormone-of-the-crustacean-daphnia-pulex-with-its-cognate-receptor-dappu-rpchr-a-nuclear-magnetic-resonance-and-modeling-study
#8
Graham E Jackson, Elumalai Pavadai, Gerd Gäde, Zaheer Timol, Niels H Andersen
The primary sequence of the red pigment-concentrating hormone (RPCH) receptor of the water flea, Daphnia pulex, was used in homology modeling to construct the first 3D model of a crustacean G-protein coupled receptor, Dappu-RPCHR. This receptor was found to belong to the class A subfamily of GPCRs with a disulfide bridge between Cys(72) and Cys(150) and an ionic lock between Arg(97) and Thr(224) and Thr(220). NMR restrained molecular dynamics was used to determine the structure of an agonist, Dappu-RPCH, in a membrane-mimicking environment...
August 22, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28770361/exploring-the-binding-energy-profiles-of-full-agonists-partial-agonists-and-antagonists-of-the-%C3%AE-7-nicotinic-acetylcholine-receptor
#9
Nargis Tabassum, Qianyun Ma, Guanzhao Wu, Tao Jiang, Rilei Yu
Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure...
September 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28762314/insights-into-nicotinic-receptor-signaling-in-nicotine-addiction-implications-for-prevention-and-treatment
#10
Wuyi Liu, Ming D Li
Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop ligand-gated ion-channel (LGIC) superfamily, which also includes the GABA, glycine, and serotonin receptors. Many nAChR subunits have been identified and shown to be involved in signal transduction on binding to them of either the neurotransmitter acetylcholine or exogenous ligands such as nicotine. The nAChRs are pentameric assemblies of homologous subunits surrounding a central pore that gates cation flux, and they are expressed at neuromuscular junctions throughout the nervous system...
August 1, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/28724750/disruption-of-a-structurally-important-extracellular-element-in-the-glycine-receptor-leads-to-decreased-synaptic-integration-and-signaling-resulting-in-severe-startle-disease
#11
Natascha Schaefer, Alexandra Berger, Johannes van Brederode, Fang Zheng, Yan Zhang, Sophie Leacock, Laura Littau, Sibylle Jablonka, Sony Malhotra, Maya Topf, Friederike Winter, Daria Davydova, Joseph W Lynch, Christopher J Paige, Christian Alzheimer, Robert J Harvey, Carmen Villmann
Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorders. We found that a lack of synaptic integration of GlyRs, together with disrupted receptor function, is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant shaky, caused by a missense mutation, Q177K, located in the extracellular β8-β9 loop of the GlyR α1 subunit. Recently, structural data provided evidence that the flexibility of the β8-β9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in Cys-loop receptors...
August 16, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28715108/ivermectin-activates-girk-channels-in-a-pip2-dependent-g%C3%AE-%C3%AE-independent-manner-and-an-amino-acid-residue-at-the-slide-helix-governs-the-activation
#12
I-Shan Chen, Michihiro Tateyama, Yuko Fukata, Motonari Uesugi, Yoshihiro Kubo
KEY POINTS: Ivermectin (IVM) is a widely used antiparasitic drug in humans and pets which activates glutamate-gated Cl(-) channel in parasites. It is known that IVM binds to the transmembrane domains (TMs) of several ligand-gated channels, such as Cys-loop receptors and P2X receptors. We found that the G-protein-gated inwardly rectifying K(+) (GIRK) channel, especially GIRK2, is activated by IVM directly in a Gβγ -independent manner, but the activation is dependent on phosphatidylinositol-4,5-biphosphate (PIP2 )...
September 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28606760/progress-in-the-discovery-of-small-molecule-modulators-of-the-cys-loop-superfamily-receptors
#13
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...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28606041/mechanisms-of-action-resistance-and-toxicity-of-insecticides-targeting-gaba-receptors
#14
REVIEW
Steven D Buckingham, Makoto Ihara, David B Sattelle, Kazuhiko Matsuda
BACKGROUND: γ-Aminobutyric acid (GABA) receptors play a central role in fast inhibitory neurotransmission in insects. Several classes of insecticides targeting insect GABA-gated chloride channels have been developed. The important resistant to dieldrin GABA receptor subunit (RDL) has been used to investigate insecticide sites of action using radioligands, electrophysiology and site-directed mutagenesis. Although this important subunit readily forms robust functional homomeric receptors when expressed, alternative splicing and RNA A-to-I editing can generate diverse forms of the receptor...
2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28513076/a-computational-assessment-of-the-predicted-structures-of-human-macrophage-migration-inhibitory-factor-1-orthologs-in-parasites-and-its-affinity-to-human-cd74-receptor
#15
Claudia Machicado, Luis A Marcos
The human macrophage migration inhibitory factor 1 (Hu-MIF-1) is a protein involved in the inflammatory and immunology response to parasite infection. In the present study, the existence of Hu-MIF-1 from parasites have been explored by mining WormBase. A total of 35 helminths were found to have Hu-MIF-1 homologs, including some parasites of importance for public health. Physicochemical, structural, and biological properties of Hu-MIF-1 were compared with its orthologs in parasites showing that most of these are secretory proteins, with positive net charge and presence of the Cys-Xaa-Xaa-Cys motif that is critical for its oxidoreductase activity...
May 17, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28479061/crystal-structures-of-human-glyr%C3%AE-3-bound-to-ivermectin
#16
Xin Huang, Hao Chen, Paul L Shaffer
Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal α7-nicotinic receptors (α7 nAChRs). The crystal structure of Caenorhabditis elegans GluCl complexed with ivermectin revealed the details of its ivermectin binding site. Although the electron microscopy structure of zebrafish GlyRα1 complexed with ivermectin demonstrated a similar binding orientation, detailed structural information on the ivermectin binding and pore opening for Cys-loop receptors in vertebrates has been elusive...
June 6, 2017: Structure
https://www.readbyqxmd.com/read/28429004/binding-site-opening-by-loop-c-shift-and-chloride-ion-pore-interaction-in-the-gabaa-receptor-model
#17
M A Michałowski, S Kraszewski, J W Mozrzymas
GABAA receptors (GABAARs) are crucial in mediating inhibition in the adult mammalian brain. Although the kinetics of this receptor has been extensively studied, the molecular picture of interactions occurring at various channel conformations remains elusive. While electrophysiology combined with mutagenesis sheds light on the role of specific residues, ultrastructural studies reveal static structures which, in the case of GABAARs, are limited to the β3 homomer. To take advantage of the newest crystal structures of cys-loop receptors, a homology model of α1β2γ2 GABAAR in the unbound closed state was built using a template of the homomeric glycine receptor in the closed state...
May 31, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28408206/towards-understanding-the-molecular-basis-of-ion-channel-modulation-by-lipids-mechanistic-models-and-current-paradigms
#18
REVIEW
José A Poveda, A Marcela Giudici, M Lourdes Renart, Andrés Morales, José M González-Ros
Research on ion channel modulation has become a hot topic because of the key roles these membrane proteins play in both prokaryotic and eukaryotic organisms. In this respect, lipid modulation adds to the overall modulatory mechanisms as a potential via to find new pharmacological targets for drug design based on interfering with lipid/channel interactions. However, our knowledge in this field is scarce and often circumscribed to the sites where lipids bind and/or its final functional consequences. To fully understand this process it is necessary to improve our knowledge on its molecular basis, from the binding sites to the signalling pathways that derive in structural and functional effects on the ion channel...
September 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28383883/the-proton-responsiveness-in-the-extracellular-domain-of-glic-differs-in-the-presence-of-the-elic-transmembrane-domain
#19
Mona A Alqazzaz, Kerry L Price, Sarah C R Lummis
Prokaryotic homologues of Cys-loop receptors have proven to be useful in understanding their eukaryotic counterparts, but even the best studied of these, Gloeobacter ligand-gated ion channel (GLIC), is still not yet fully understood. GLIC is activated by protons with a pH50 between 5 and 6, implicating a histidine residue in its activation, but although a histidine residue (His11') in the pore-forming α-helix (M2) is known to be involved in gating, the His in the extracellular domain (ECD), His127, is not...
April 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28367632/subtle-differences-among-5-ht3ac-5-ht3ad-and-5-ht3ae-receptors-are-revealed-by-partial-agonists
#20
Kerry L Price, Yuri Hirayama, Sarah C R Lummis
5-HT3 receptors are members of the Cys-loop family of ligand-gated ion channels, and, like most members of this family, there are multiple subunits that can contribute to functional pentameric receptors. 5-HT3A and 5-HT3AB receptors have been extensively characterized, but there are few studies on 5-HT3AC, 5-HT3AD, and 5-HT3AE receptors. Here we explore the properties of a range of partial agonists at 5-HT3AC, 5-HT3AD, and 5-HT3AE receptors following expression in Xenopus oocytes. The data show that the characteristics of receptor activation differ in the different heteromeric receptors when they are challenged with 5-HT, m-chlorophenylbiguanide (mCPBG), varenicline, 5-fluorotryptamine (5-FT), or thymol...
April 3, 2017: ACS Chemical Neuroscience
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