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Cys loop receptor

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
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 3, 2016: Nature
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 with HEK293 cells stably expressing the 5-HT3 receptor...
September 28, 2016: British Journal of Pharmacology
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...
September 23, 2016: Biochimica et Biophysica Acta
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...
September 24, 2016: Neuropharmacology
Hongxia Liu, Andrew S French, Päivi H Torkkeli
The spider, Cupiennius salei, central and peripheral nervous system transcriptomes 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
Dinesh C Indurthi, Trevor M Lewis, Philip K Ahring, Thomas Balle, Mary Chebib, Nathan L Absalom
The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant subtype in the brain and exists in two functional stoichiometries: (α4)3(β2)2 and (α4)2(β2)3. A distinct feature of the (α4)3(β2)2 receptor is the biphasic activation response to the endogenous agonist acetylcholine, where it is activated with high potency and low efficacy when two α4-β2 binding sites are occupied and with low potency/high efficacy when a third α4-α4 binding site is occupied. Further, exogenous ligands can bind to the third α4-α4 binding site and potentiate the activation of the receptor by ACh that is bound at the two α4-β2 sites...
2016: PloS One
G Faure, I V Shelukhina, D Porowinska, M A Shulepko, E N Lyukmanova, D A Dolgikh, E N Spirova, I E Kasheverov, Yu N Utkin, J-P Corringer, V I Tsetlin
With the use of surface plasmon resonance (SPR) it was shown that ws-Lynx1, a water-soluble analog of the three-finger membrane-bound protein Lynx1, that modulates the activity of brain nicotinic acetylcholine receptors (nAChRs), interacts with the acetylcholine-binding protein (AChBP) with high affinity, K D = 62 nM. This result agrees with the earlier demonstrated competition of ws-Lynx1 with radioiodinated α-bungarotoxin for binding to AChBP. For the first time it was shown that ws-Lynx1 binds to GLIC, prokaryotic Cys-loop receptor (K D = 1...
May 2016: Doklady. Biochemistry and Biophysics
Clara Stead, Adam Brown, Cathryn Adams, Sarah J Nickolls, Gareth Young, Juha Kammonen, David Pryde, Darren Cawkill
Glycine receptor 3 (GlyRα3) is a ligand-gated ion channel of the cys-loop family that plays a key role in mediating inhibitory neurotransmission and regulation of pain signaling in the dorsal horn. Potentiation of GlyRα3 function is therefore of interest as a putative analgesic mechanism with which to target new therapeutics. However, to date, positive allosteric modulators (PAMs) of this receptor with sufficient selectivity to enable target validation studies have not been described. To address this lack of pharmacological tools, we developed a suite of in vitro assays comprising a high-throughput fluorescent membrane potential screen and a medium-throughput electrophysiology assay using IonFlux HT together with conventional manual patch clamp...
July 7, 2016: Journal of Biomolecular Screening
Carlos F Burgos, Gonzalo E Yévenes, Luis G Aguayo
Glycine receptors (GlyR) are inhibitory Cys-loop ion channels that contribute to the control of excitability along the central nervous system (CNS). GlyR are found in the spinal cord and brain stem, and more recently they were reported in higher regions of the CNS such as the hippocampus and nucleus accumbens. GlyR are involved in motor coordination, respiratory rhythms, pain transmission, and sensory processing, and they are targets for relevant physiologic and pharmacologic modulators. Several studies with protein crystallography and cryoelectron microscopy have shed light on the residues and mechanisms associated with the activation, blockade, and regulation of pentameric Cys-loop ion channels at the atomic level...
September 2016: Molecular Pharmacology
Tommy S Tillman, Frances J D Alvarez, Nathan J Reinert, Chuang Liu, Dawei Wang, Yan Xu, Kunhong Xiao, Peijun Zhang, Pei Tang
Human Cys-loop receptors are important therapeutic targets. High-resolution structures are essential for rational drug design, but only a few are available due to difficulties in obtaining sufficient quantities of protein suitable for structural studies. Although expression of proteins in E. coli offers advantages of high yield, low cost, and fast turnover, this approach has not been thoroughly explored for full-length human Cys-loop receptors because of the conventional wisdom that E. coli lacks the specific chaperones and post-translational modifications potentially required for expression of human Cys-loop receptors...
August 26, 2016: Journal of Biological Chemistry
Roshan Puthenkalam, Marcel Hieckel, Xenia Simeone, Chonticha Suwattanasophon, Roman V Feldbauer, Gerhard F Ecker, Margot Ernst
Atomic resolution structures of cys-loop receptors, including one of a γ-aminobutyric acid type A receptor (GABAA receptor) subtype, allow amazing insights into the structural features and conformational changes that these pentameric ligand-gated ion channels (pLGICs) display. Here we present a comprehensive analysis of more than 30 cys-loop receptor structures of homologous proteins that revealed several allosteric binding sites not previously described in GABAA receptors. These novel binding sites were examined in GABAA receptor homology models and assessed as putative candidate sites for allosteric ligands...
2016: Frontiers in Molecular Neuroscience
Heather D Snell, Eric B Gonzales
Guanidine compounds act as ion channel modulators. In the case of Cys-loop receptors, the guanidine compound amiloride antagonized the heteromeric GABA-A, glycine, and nicotinic acetylcholine receptors. However, amiloride exhibits characteristics consistent with a positive allosteric modulator for the human GABA-A (hGABA-A) ρ1 receptor. Site-directed mutagenesis revealed that the positive allosteric modulation was influenced by the GABA-A ρ1 second transmembrane domain 15' position, a site implicated in ligand allosteric modulation of Cys-loop receptors...
November 2016: Channels
Nuriya Mukhtasimova, Corrie J B daCosta, Steven M Sine
The acetylcholine receptor (AChR) from vertebrate skeletal muscle initiates voluntary movement, and its kinetics of activation are crucial for maintaining the safety margin for neuromuscular transmission. Furthermore, the kinetic mechanism of the muscle AChR serves as an archetype for understanding activation mechanisms of related receptors from the Cys-loop superfamily. Here we record currents through single muscle AChR channels with improved temporal resolution approaching half an order of magnitude over our previous best...
July 2016: Journal of General Physiology
Georg Langlhofer, Carmen Villmann
The family of Cys-loop receptors (CLRs) shares a high degree of homology and sequence identity. The overall structural elements are highly conserved with a large extracellular domain (ECD) harboring an α-helix and 10 β-sheets. Following the ECD, four transmembrane domains (TMD) are connected by intracellular and extracellular loop structures. Except the TM3-4 loop, their length comprises 7-14 residues. The TM3-4 loop forms the largest part of the intracellular domain (ICD) and exhibits the most variable region between all CLRs...
2016: Frontiers in Molecular Neuroscience
Andrew J R Plested
Ion channels gated by neurotransmitters are present across metazoans, in which they are essential for brain function, sensation and locomotion; closely related homologs are also found in bacteria. Structures of eukaryotic pentameric cysteine-loop (Cys-loop) receptors and tetrameric ionotropic glutamate receptors in multiple functional states have recently become available. Here, I describe how these studies relate to established ideas regarding receptor activation and how they have enabled decades' worth of functional work to be pieced together, thus allowing previously puzzling aspects of receptor activity to be understood...
June 7, 2016: Nature Structural & Molecular Biology
Federico Comitani, Vittorio Limongelli, Carla Molteni
Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop superfamily are important neuroreceptors that mediate fast synaptic transmission. They are activated by the binding of a neurotransmitter, but the details of this process are still not fully understood. As a prototypical pLGIC, here we choose the insect resistance to dieldrin (RDL) receptor involved in resistance to insecticides and investigate the binding of the neurotransmitter GABA to its extracellular domain at the atomistic level. We achieve this by means of μ-sec funnel-metadynamics simulations, which efficiently enhance the sampling of bound and unbound states by using a funnel-shaped restraining potential to limit the exploration in the solvent...
July 12, 2016: Journal of Chemical Theory and Computation
Line Barington, Pia C Rummel, Michael Lückmann, Heidi Pihl, Olav Larsen, Viktorija Daugvilaite, Anders H Johnsen, Thomas M Frimurer, Stefanie Karlshøj, Mette M Rosenkilde
Chemokine receptors play important roles in the immune system and are linked to several human diseases. The initial contact of chemokines with their receptors depends on highly specified extracellular receptor features. Here we investigate the importance of conserved extracellular disulfide bridges and aromatic residues in extracellular loop 2 (ECL-2) for ligand binding and activation in the chemokine receptor CCR8. We used inositol 1,4,5-trisphosphate accumulation and radioligand binding experiments to determine the impact of receptor mutagenesis on both chemokine and small molecule agonist and antagonist binding and action in CCR8...
July 29, 2016: Journal of Biological Chemistry
Daniel T Baptista-Hon, Alexander Krah, Ulrich Zachariae, Tim G Hales
KEY POINTS: The role of the β1 strand in GABAA receptor function is unclear. It lies anti-parallel to the β2 strand, which is known to participate in receptor activation. Molecular dynamics simulation revealed solvent accessible residues within the β1 strand of the GABAA β3 homopentamer that might be amenable to analysis using the substituted Cys accessibility method. Cys substitutions from Asp43 to Thr47 in the GABAA α1 subunit showed that D43C and T47C reduced the apparent potency of GABA...
October 1, 2016: Journal of Physiology
Agnes Gasiorek, Sarah M Trattnig, Philip K Ahring, Uffe Kristiansen, Bente Frølund, Kristen Frederiksen, Anders A Jensen
We have previously identified a novel class of 5-hydroxytryptamine type 3 receptor (5-HT3R) agonists sharing little structural similarity with orthosteric 5-HT3R ligands (Jørgensen et al., 2011). In the present study we have elucidated the functional characteristics and the mechanism of action of one of these compounds, trans-3-(4-methoxyphenyl)-N-(pentan-3-yl)acrylamide (TMPPAA). In electrophysiological recordings TMPPAA was found to be a highly-efficacious partial agonist equipotent with 5-HT at the 5-HT3A receptor (5-HT3AR) expressed in COS-7 cells and somewhat less potent at the receptor expressed in Xenopus oocytes...
June 15, 2016: Biochemical Pharmacology
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