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Cys loop receptor

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https://www.readbyqxmd.com/read/28429004/binding-site-opening-by-loop-c-shift-and-chloride-ion-pore-interaction-in-the-gabaa-receptor-model
#1
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...
April 21, 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
#2
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
#3
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 6, 2017: Biochemistry
https://www.readbyqxmd.com/read/28367632/subtle-differences-among-5-ht3ac-5-ht3ad-and-5-ht3ae-receptors-are-revealed-by-partial-agonists
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/27791038/allosteric-binding-site-in-a-cys-loop-receptor-ligand-binding-domain-unveiled-in-the-crystal-structure-of-elic-in-complex-with-chlorpromazine
#13
Mieke Nys, Eveline Wijckmans, Ana Farinha, Özge Yoluk, Magnus Andersson, Marijke Brams, Radovan Spurny, Steve Peigneur, Jan Tytgat, Erik Lindahl, Chris Ulens
Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27782882/release-dependent-feedback-inhibition-by-a-presynaptically-localized-ligand-gated-anion-channel
#14
Seika Takayanagi-Kiya, Keming Zhou, Yishi Jin
Presynaptic ligand-gated ion channels (LGICs) have long been proposed to affect neurotransmitter release and to tune the neural circuit activity. However, the understanding of their in vivo physiological action remains limited, partly due to the complexity in channel types and scarcity of genetic models. Here we report that C. elegans LGC-46, a member of the Cys-loop acetylcholine (ACh)-gated chloride (ACC) channel family, localizes to presynaptic terminals of cholinergic motor neurons and regulates synaptic vesicle (SV) release kinetics upon evoked release of acetylcholine...
October 26, 2016: ELife
https://www.readbyqxmd.com/read/27739668/crotonic-acid-blocks-the-gloeobacter-ligand-gated-ion-channel-glic-via-the-extracellular-domain
#15
Mona A Alqazzaz, Kerry L Price, Sarah C R Lummis
Cys-loop receptors play important roles in signal transduction in multicellular organisms, but similar proteins exist in prokaryotes, the best studied of which is the Gloeobacter ligand-gated ion channel (GLIC). GLIC is activated by protons with 50% activation (pH50) at pH 5.5, and while a histidine residue in its pore-forming α-helix (M2) is known to be involved in gating, there is also evidence of a proton-sensitive region in the extracellular domain. However, this proton-sensitive region does not appear to be located in the region of GLIC equivalent to the agonist binding site in related proteins...
October 14, 2016: Biochemistry
https://www.readbyqxmd.com/read/27698419/x-ray-structure-of-the-human-%C3%AE-4%C3%AE-2-nicotinic-receptor
#16
Claudio L Morales-Perez, Colleen M Noviello, Ryan E Hibbs
Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have diverse signalling roles in the central nervous system. The nicotinic receptor has been a model system for cell-surface receptors, and specifically for ligand-gated ion channels, for well over a century. In addition to the receptors' prominent roles in the development of the fields of pharmacology and neurobiology, nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery...
October 20, 2016: Nature
https://www.readbyqxmd.com/read/27677804/novel-mechanism-of-modulation-at-a-ligand-gated-ion-channel-action-of-5-cl-indole-at-the-5-ht3-a-receptor
#17
Andrew D Powell, Gillian Grafton, Alexander Roberts, Shannon Larkin, Nathanael O'Neill, Josephine Palandri, Reka Otvos, Alison J Cooper, Chris Ulens, Nicholas M Barnes
BACKGROUND AND PURPOSE: The 5-HT3 receptor is a prototypical member of the Cys-loop ligand-gated ion channel (LGIC) superfamily and an established therapeutic target. In addition to activation via the orthosteric site, receptor function can be modulated by allosteric ligands. We have investigated the pharmacological action of Cl-indole upon the 5-HT3 A receptor and identified that this positive allosteric modulator possesses a novel mechanism of action for LGICs. EXPERIMENTAL APPROACH: The impact of Cl-indole upon the 5-HT3 receptor was assessed using single cell electrophysiological recordings and [(3) H]-granisetron binding in HEK293 cells stably expressing the 5-HT3 receptor...
December 2016: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27671350/apelin-binding-to-human-apj-receptor-leads-to-biased-signaling
#18
Prashant Kumar, Anisha Ashokan, Gopala Krishna Aradhyam
BACKGROUND: Human APJ receptor (APJR), a rhodopsin family G-Protein Coupled Receptor (GPCR), activated by isoforms of peptide ligand apelin causing potent inotropic effect, is involved in cardiac function, angiogenesis and maintenance of fluid homeostasis. APJR is expressed in various organs e.g., heart, brain, kidney, muscles, etc. Hence, problems in APJR signaling lead to severe dysregulation in the pathophysiology of an organism. METHODS: Based on multiple sequence alignment of receptors from various organisms, we observe a large number of conserved residues in the extracellular side...
December 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27671323/the-antidepressant-bupropion-is-a-negative-allosteric-modulator-of-serotonin-type-3a-receptors
#19
Akash Pandhare, Aneesh Satya Pappu, Henrik Wilms, Michael Paul Blanton, Michaela Jansen
The FDA-approved antidepressant and smoking cessation drug bupropion is known to inhibit dopamine and norepinephrine reuptake transporters, as well as nicotinic acetylcholine receptors (nAChRs) which are cation-conducting members of the Cys-loop superfamily of ion channels, and more broadly pentameric ligand-gated ion channels (pLGICs). In the present study, we examined the ability of bupropion and its primary metabolite hydroxybupropion to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs), and further characterized bupropion's pharmacological effects at these receptors...
February 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27650259/expression-of-cys-loop-receptor-subunits-and-acetylcholine-binding-protein-in-the-mechanosensory-neurons-glial-cells-and-muscle-tissue-of-the-spider-cupiennius-salei
#20
Hongxia Liu, Andrew S French, Päivi H Torkkeli
The central and peripheral nervous system transcriptomes of the spider Cupiennius salei have 15 Cys-loop receptor subunits and an acetylcholine-binding protein (AChBP). Twelve subunits are predicted to form anion channels gated by γ-aminobutyric acid (GABA), glutamate, histamine, or changes in pH, and three are putative ACh-gated cation channels. Spiders have a variety of mechanosensilla and proprioceptive organs that are innervated by efferents in their peripherally located parts, and efferents also innervate muscle fibers...
September 21, 2016: Journal of Comparative Neurology
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