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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
#1
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
#2
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
#3
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 disorder. We found that 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...
July 19, 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
#4
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 )...
July 17, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28606760/progress-in-the-discovery-of-small-molecule-modulators-of-the-cys-loop-superfamily-receptors
#5
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
#6
Steven Buckingham, Makoto Ihara, David B Sattelle, Kazuhiko Matsuda
Ionotropic γ-aminobutyric acid (GABA)-gated chloride channels belong to the cys-loop superfamily of ligand-gated ion channels (cys-loop LGICs) and mediate fast inhibitory synaptic transmission in the nervous system and at neuromuscular junctions of insects. Insect GABA-gated cation channels have also been described. The sequencing of insect genomes has enhanced our understanding of the subunits that make up GABA receptor gene families of many species, including a genetic model organism (Drosophila melanogaster) as well as pest, vector and beneficial (pollinator) species...
June 12, 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
#7
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
#8
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
#9
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
#10
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...
April 11, 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
#11
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
#12
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
https://www.readbyqxmd.com/read/28187828/molecular-characterization-and-expression-pattern-of-three-gaba-receptor-like-subunits-in-the-small-brown-planthopper-laodelphax-striatellus-hemiptera-delphacidae
#13
Qi Wei, Shun-Fan Wu, Cong-Fen Gao
Ionotropic γ-aminobutyric acid (GABA)-gated chloride channel receptors mediate rapid inhibitory neurotransmission in vertebrates and invertebrates. GABA receptors are well known to be the molecular targets of synthetic insecticides or parasiticides. Three GABA receptor-like subunits, LsLCCH3, LsGRD and LS8916, of the small brown planthopper, Laodelphax striatellus (Fallén), a major insect pest of crop systems in East Asia, had been identified and characterized in this study. All three genes were cloned using the reverse transcriptase polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE)...
March 2017: Pesticide Biochemistry and Physiology
https://www.readbyqxmd.com/read/28176635/modes-of-action-resistance-and-toxicity-of-insecticides-targeting-nicotinic-acetylcholine-receptors
#14
Makoto Ihara, Steven D Buckingham, Kazuhiko Matsuda, David B Sattelle
Nicotinic acetylcholine receptors (nAChRs) are members of the cys-loop superfamily of ligand-gated ion channels (cys-loop LGICs) and mediate fast cholinergic synaptic transmission in the nervous system of insects. The completion of many insect genome projects has greatly enhanced our understanding of the individual subunits that make up nAChR gene families from an insect genetic model organism (Drosophila melanogaster), crop pests, disease vectors and beneficial (pollinator) species. In addition to considerable insect nAChR subunit diversity, individual subunits can be subject to alternative splicing and RNA editing and these post-transcriptional modifications can add significantly to the diversity of nAChR receptor subtypes...
February 6, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28146602/pharmacological-characterization-of-the-excitatory-cys-loop-gaba-receptor-family-in-caenorhabditis-elegans
#15
Georgina C B Nicholl, Ali K Jawad, Robert Weymouth, Haoming Zhang, Asim A Beg
BACKGROUND AND PURPOSE: Ionotropic GABA receptors are evolutionarily conserved proteins that mediate cellular and network inhibition in both vertebrates and invertebrates. A unique class of excitatory GABA receptors has been identified in several nematode species. Despite well-characterized functions in Caenorhabditis elegans, little is known about the pharmacology of the excitatory GABA receptors EXP-1 and LGC-35. Using a panel of compounds that differentially activate and modulate ionotropic GABA receptors, we investigated the agonist binding site and allosteric modulation of EXP-1 and LGC-35...
May 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28121133/probing-the-structural-mechanism-of-partial-agonism-in-glycine-receptors-using-the-fluorescent-artificial-amino-acid-anap
#16
Ming S Soh, Argel Estrada-Mondragon, Nela Durisic, Angelo Keramidas, Joseph W Lynch
The efficacy of an agonist at a pentameric ligand-gated ion channel is determined by the rate at which it induces a conformational change from the resting closed state to a preopen ("flip") state. If the ability of an agonist to promote this isomerization is sufficiently low, then it becomes a partial agonist. As partial agonists at pentameric ligand-gated ion channels show considerable promise as therapeutics, understanding the structural basis of the resting-flip-state isomerization may provide insight into therapeutic design...
March 17, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/27981574/loop-g-in-the-gabaa-receptor-%C3%AE-1-subunit-influences-gating-efficacy
#17
Daniel T Baptista-Hon, Simona Gulbinaite, Tim G Hales
KEY POINTS: The functional importance of residues in loop G of the GABAA receptor has not been investigated. D43 and T47 in the α1 subunit are of particular significance as their structural modification inhibits activation by GABA. While the T47C substitution had no significant effect, non-conservative substitution of either residue (D43C or T47R) reduced the apparent potency of GABA. Propofol potentiated maximal GABA-evoked currents mediated by α1(D43C)β2γ2 and α1(T47R)β2γ2 receptors...
March 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/27923639/disruption-of-a-putative-intersubunit-electrostatic-bond-enhances-agonist-efficacy-at-the-human-%C3%AE-1-glycine-receptor
#18
Brian T Welsh, Jelena Todorovic, Dean Kirson, Hunter M Allen, Michelle D Bayly, S John Mihic
Partial agonists have lower efficacies than compounds considered 'full agonists', eliciting submaximal responses even at saturating concentrations. Taurine is a partial agonist at the glycine receptor (GlyR), a member of the cys-loop ligand-gated ion channel superfamily. The molecular mechanisms responsible for agonism are not fully understood but evidence suggests that efficacy at these receptors is determined by conformational changes that occur early in the process of receptor activation. We previously identified a residue located near the human α1 glycine binding site (aspartate-97; D97) that, when mutated to arginine (D97R), results in GlyR channels opening spontaneously with a high open probability, mimicking the effects of saturating glycine concentrations on wildtype GlyR...
February 15, 2017: Brain Research
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
#19
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 are thought to act on elements of the pathways that couple agonist binding to channel gating. Using α4β2 nicotinic acetylcholine receptors 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 pentameric ligand-gated ion channels. Previous studies have shown that the binding site for potentiating βEST is in the C-terminal (post-M4) region of the α4 subunit...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27816008/in-silico-investigation-into-the-interactions-between-murine-5-ht3-receptor-and-the-principle-active-compounds-of-ginger-zingiber-officinale
#20
Anna E Lohning, Wolfgang Marx, Liz Isenring
Gingerols and shogaols are the primary non-volatile actives within ginger (Zingiber officinale). These compounds have demonstrated in vitro to exert 5-HT3 receptor antagonism which could benefit chemotherapy-induced nausea and vomiting (CINV). The site and mechanism of action by which these compounds interact with the 5-HT3 receptor is not fully understood although research indicates they may bind to a currently unidentified allosteric binding site. Using in silico techniques, such as molecular docking and GRID analysis, we have characterized the recently available murine 5-HT3 receptor by identifying sites of strong interaction with particular functional groups at both the orthogonal (serotonin) site and a proposed allosteric binding site situated at the interface between the transmembrane region and the extracellular domain...
November 2016: Journal of Molecular Graphics & Modelling
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