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[PMID]:29069080
[Au] Autor:Martin NE; Malik S; Calimet N; Changeux JP; Cecchini M
[Ad] Endereço:Laboratoire d'Ingénierie des Fonctions Moléculaire, ISIS, UMR 7006 CNRS, Université de Strasbourg, Strasbourg, France.
[Ti] Título:Un-gating and allosteric modulation of a pentameric ligand-gated ion channel captured by molecular dynamics.
[So] Source:PLoS Comput Biol;13(10):e1005784, 2017 Oct.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pentameric ligand-gated ion channels (pLGICs) mediate intercellular communication at synapses through the opening of an ion pore in response to the binding of a neurotransmitter. Despite the increasing availability of high-resolution structures of pLGICs, a detailed understanding of the functional isomerization from closed to open (gating) and back is currently missing. Here, we provide the first atomistic description of the transition from open to closed (un-gating) in the glutamate-gated chloride channel (GluCl) from Caenorhabditis Elegans. Starting with the active-state structure solved in complex with the neurotransmitter L-glutamate and the positive allosteric modulator (PAM) ivermectin, we analyze the spontaneous relaxation of the channel upon removal of ivermectin by explicit solvent/membrane Molecular Dynamics (MD) simulations. The µs-long trajectories support the conclusion that ion-channel deactivation is mediated by two distinct quaternary transitions, i.e. a global receptor twisting followed by the radial expansion (or blooming) of the extracellular domain. At variance with previous models, we show that pore closing is exclusively regulated by the global twisting, which controls the position of the ß1-ß2 loop relative to the M2-M3 loop at the EC/TM domain interface. Additional simulations with L-glutamate restrained to the crystallographic binding mode and ivermectin removed indicate that the same twisting isomerization is regulated by agonist binding at the orthosteric site. These results provide a structural model for gating in pLGICs and suggest a plausible mechanism for the pharmacological action of PAMs in this neurotransmitter receptor family. The simulated un-gating converges to the X-ray structure of GluCl resting state both globally and locally, demonstrating the predictive character of state-of-art MD simulations.
[Mh] Termos MeSH primário: Regulação Alostérica
Ácido Glutâmico/química
Ativação do Canal Iônico
Ivermectina/química
Ligantes
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Sítio Alostérico
Sítios de Ligação
Canais de Cloreto/química
Canais de Cloreto/ultraestrutura
Canais Iônicos de Abertura Ativada por Ligante/química
Canais Iônicos de Abertura Ativada por Ligante/ultraestrutura
Modelos Químicos
Neurotransmissores/química
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chloride Channels); 0 (Ligand-Gated Ion Channels); 0 (Ligands); 0 (Neurotransmitter Agents); 0 (glutamate-gated chloride channels); 3KX376GY7L (Glutamic Acid); 70288-86-7 (Ivermectin)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171026
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005784


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[PMID]:28887352
[Au] Autor:Nakata Y; Fuse T; Yamato K; Asahi M; Nakahira K; Ozoe F; Ozoe Y
[Ad] Endereço:Faculty of Life and Environmental Science, Shimane University, Matsue, Shimane, Japan (Y.N., T.F., K.Y, F.O., Y.O.); and Biological Research Laboratories, Nissan Chemical Industries, Ltd., Saitama, Japan (M.A., K.N.).
[Ti] Título:A Single Amino Acid Substitution in the Third Transmembrane Region Has Opposite Impacts on the Selectivity of the Parasiticides Fluralaner and Ivermectin for Ligand-Gated Chloride Channels.
[So] Source:Mol Pharmacol;92(5):546-555, 2017 Nov.
[Is] ISSN:1521-0111
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fluralaner (Bravecto) is a recently marketed isoxazoline ectoparasiticide. This compound potently inhibits GABA-gated chloride channels (GABACls) and less potently glutamate-gated chloride channels (GluCls) in insects. The mechanism underlying this selectivity is unknown. Therefore, we sought to identify the amino acid residues causing the low potency of fluralaner toward GluCls. We examined the fluralaner sensitivity of mutant housefly ( ) GluCls in which amino acid residues in the transmembrane subunit interface were replaced with the positionally equivalent amino acids of GABACls. Of these amino acids, substitution of an amino acid (Leu315) in the third transmembrane region (TM3) with an aromatic amino acid dramatically enhanced the potency of fluralaner in the GluCls. In stark contrast to the enhancement of fluralaner potency, this mutation eliminated the activation of currents and the potentiation but not the antagonism of glutamate responses that are otherwise all elicited by the macrolide parasiticide ivermectin (IVM). Our findings indicate that the amino acid Leu315 in GluCls plays significant roles in determining the selectivity of fluralaner and IVM for these channels. Given the high sequence similarity of TM3, this may hold true more widely for the GluCls and GABACls of other insect species.
[Mh] Termos MeSH primário: Substituição de Aminoácidos/genética
Antiparasitários/farmacologia
Canais de Cloreto/genética
Isoxazóis/farmacologia
Ivermectina/farmacologia
Canais Iônicos de Abertura Ativada por Ligante/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos/efeitos dos fármacos
Animais
Antiparasitários/metabolismo
Caenorhabditis elegans
Canais de Cloreto/química
Canais de Cloreto/metabolismo
Relação Dose-Resposta a Droga
Feminino
Moscas Domésticas
Inseticidas/metabolismo
Inseticidas/farmacologia
Isoxazóis/metabolismo
Ivermectina/metabolismo
Canais Iônicos de Abertura Ativada por Ligante/química
Canais Iônicos de Abertura Ativada por Ligante/metabolismo
Estrutura Secundária de Proteína
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (A1443 compound); 0 (Antiparasitic Agents); 0 (Chloride Channels); 0 (Insecticides); 0 (Isoxazoles); 0 (Ligand-Gated Ion Channels); 70288-86-7 (Ivermectin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170910
[St] Status:MEDLINE
[do] DOI:10.1124/mol.117.109413


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[PMID]:28793215
[Au] Autor:Ion BF; Wells MM; Chen Q; Xu Y; Tang P
[Ad] Endereço:Departments of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
[Ti] Título:Ketamine Inhibition of the Pentameric Ligand-Gated Ion Channel GLIC.
[So] Source:Biophys J;113(3):605-612, 2017 Aug 08.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ketamine inhibits pentameric ligand-gated ion channels (pLGICs), including the bacterial pLGIC from Gloeobacter violaceus (GLIC). The crystal structure of GLIC shows R-ketamine bound to an extracellular intersubunit cavity. Here, we performed molecular dynamics simulations of GLIC in the absence and presence of R- or S-ketamine. No stable binding of S-ketamine in the original cavity was observed in the simulations, largely due to its unfavorable access to residue D154, which provides important electrostatic interactions to stabilize R-ketamine binding. Contrary to the symmetric binding shown in the crystal structure, R-ketamine moved away from some of the binding sites and was bound to GLIC asymmetrically at the end of simulations. The asymmetric binding is consistent with the experimentally measured negative cooperativity of ketamine binding to GLIC. In the presence of R-ketamine, all subunits showed changes in structure and dynamics, irrespective of binding stability; the extracellular intersubunit cavity expanded and intersubunit electrostatic interactions involved in channel activation were altered. R-ketamine binding promoted a conformational shift toward closed GLIC. Conformational changes near the ketamine-binding site were propagated to the interface between the extracellular and transmembrane domains, and further to the pore-lining TM2 through two pathways: pre-TM1 and the ß1-ß2 loop. Both signaling pathways have been predicted previously using the perturbation-based Markovian transmission model. The study provides a structural and dynamics basis for the inhibitory modulation of ketamine on pLGICs.
[Mh] Termos MeSH primário: Ketamina/farmacologia
Canais Iônicos de Abertura Ativada por Ligante/antagonistas & inibidores
Canais Iônicos de Abertura Ativada por Ligante/química
Simulação de Dinâmica Molecular
Multimerização Proteica
[Mh] Termos MeSH secundário: Ativação do Canal Iônico/efeitos dos fármacos
Ketamina/metabolismo
Canais Iônicos de Abertura Ativada por Ligante/metabolismo
Estrutura Quaternária de Proteína
Eletricidade Estática
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligand-Gated Ion Channels); 690G0D6V8H (Ketamine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170831
[Lr] Data última revisão:
170831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE


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[PMID]:28420728
[Au] Autor:Arcario MJ; Mayne CG; Tajkhorshid E
[Ad] Endereço:From the Center for Biophysics and Quantitative Biology.
[Ti] Título:A membrane-embedded pathway delivers general anesthetics to two interacting binding sites in the ion channel.
[So] Source:J Biol Chem;292(23):9480-9492, 2017 Jun 09.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:General anesthetics exert their effects on the central nervous system by acting on ion channels, most notably pentameric ligand-gated ion channels. Although numerous studies have focused on pentameric ligand-gated ion channels, the details of anesthetic binding and channel modulation are still debated. A better understanding of the anesthetic mechanism of action is necessary for the development of safer and more efficacious drugs. Herein, we present a computational study identifying two anesthetic binding sites in the transmembrane domain of the ligand-gated ion channel (GLIC) channel, characterize the putative binding pathway, and observe structural changes associated with channel function. Molecular simulations of desflurane reveal a binding pathway to GLIC via a membrane-embedded tunnel using an intrasubunit protein lumen as the conduit, an observation that explains the Meyer-Overton hypothesis, or why the lipophilicity of an anesthetic and its potency are generally proportional. Moreover, employing high concentrations of ligand led to the identification of a second transmembrane site (TM2) that inhibits dissociation of anesthetic from the TM1 site and is consistent with the high concentrations of anesthetics required to achieve clinical effects. Finally, asymmetric binding patterns of anesthetic to the channel were found to promote an iris-like conformational change that constricts and dehydrates the ion pore, creating a 13.5 kcal/mol barrier to ion translocation. Together with previous studies, the simulations presented herein demonstrate a novel anesthetic binding site in GLIC that is accessed through a membrane-embedded tunnel and interacts with a previously known site, resulting in conformational changes that produce a non-conductive state of the channel.
[Mh] Termos MeSH primário: Anestésicos Inalatórios/química
Proteínas de Bactérias
Membrana Celular
Cianobactérias
Isoflurano/análogos & derivados
Canais Iônicos de Abertura Ativada por Ligante
[Mh] Termos MeSH secundário: Proteínas de Bactérias/química
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Membrana Celular/química
Membrana Celular/metabolismo
Cianobactérias/química
Cianobactérias/metabolismo
Transporte de Íons/fisiologia
Isoflurano/química
Canais Iônicos de Abertura Ativada por Ligante/química
Canais Iônicos de Abertura Ativada por Ligante/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics, Inhalation); 0 (Bacterial Proteins); 0 (Ligand-Gated Ion Channels); CRS35BZ94Q (desflurane); CYS9AKD70P (Isoflurane)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170618
[Lr] Data última revisão:
170618
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170420
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.780197


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[PMID]:28412906
[Au] Autor:Zhang C; Li Z; Ma J; Zhang J; Zhang L; Li T; Zheng S
[Ad] Endereço:Department of Anesthesiology, Yantai Yuhuangding Hospital, Affiliated Hospital of Medical College, Qingdao University, Shandong 264000. China.
[Ti] Título:Combined Approach of QSAR and Docking Studies for the Design of Local Anaesthetic Agents.
[So] Source:Comb Chem High Throughput Screen;20(3):272-276, 2017.
[Is] ISSN:1875-5402
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Heterocyclic scaffold, benzotriazole and its derivatives are potential anaesthetic agents that act locally. OBJECTIVE: QSAR and docking analysis of previously synthesized benzotriazolyl derivatives were modelled for their local anaesthetic action using computer assisted multiple regression analysis. It provides the insight about the structural requirements for the local anaesthetic action. METHOD: A training set comprising of 16 molecules and test set of 8 molecules were selected for present investigation by using sphere exclusion method with dissimilarity value of +4.0. The validation of the QSAR models was performed by cross-validation and external test set prediction. Docking studies was performed using GRIP docking methodology. RESULTS & CONCLUSION: Further GRIP docking with the pentameric ligand gated ion channel, 2XQ3 facilitated the mechanistic analysis of interactions of the test molecules active site residues.
[Mh] Termos MeSH primário: Anestésicos Locais/química
Desenho de Drogas
[Mh] Termos MeSH secundário: Anestésicos Locais/metabolismo
Domínio Catalítico
Seres Humanos
Canais Iônicos de Abertura Ativada por Ligante/metabolismo
Simulação de Acoplamento Molecular
Relação Quantitativa Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics, Local); 0 (Ligand-Gated Ion Channels)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170803
[Lr] Data última revisão:
170803
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170418
[St] Status:MEDLINE
[do] DOI:10.2174/138620732003170803113816


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[PMID]:28279818
[Au] Autor:Elberson BW; Whisenant TE; Cortes DM; Cuello LG
[Ad] Endereço:Department of Cell Physiology and Molecular Biophysics and Center for Membrane Protein Research, Texas Tech University Health Sciences Center, 3601 4th Street STOP 6551, Lubbock, TX 79430, USA.
[Ti] Título:A cost-effective protocol for the over-expression and purification of fully-functional and more stable Erwinia chrysanthemi ligand-gated ion channel.
[So] Source:Protein Expr Purif;133:177-186, 2017 May.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Erwinia chrysanthemi ligand-gated ion channel, ELIC, is considered an excellent structural and functional surrogate for the whole pentameric ligand-gated ion channel family. Despite its simplicity, ELIC is structurally capable of undergoing ligand-dependent activation and a concomitant desensitization process. To determine at the molecular level the structural changes underlying ELIC's function, it is desirable to produce large quantities of protein. This protein should be properly folded, fully-functional and amenable to structural determinations. In the current paper, we report a completely new protocol for the expression and purification of milligram quantities of fully-functional, more stable and crystallizable ELIC. The use of an autoinduction media and inexpensive detergents during ELIC extraction, in addition to the high-quality and large quantity of the purified channel, are the highlights of this improved biochemical protocol.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Proteínas de Bactérias/isolamento & purificação
Canais Iônicos de Abertura Ativada por Ligante/química
Canais Iônicos de Abertura Ativada por Ligante/isolamento & purificação
Pectobacterium chrysanthemi/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Ligand-Gated Ion Channels)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE


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[PMID]:27916519
[Au] Autor:Chen Q; Wells MM; Tillman TS; Kinde MN; Cohen A; Xu Y; Tang P
[Ad] Endereço:Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
[Ti] Título:Structural Basis of Alcohol Inhibition of the Pentameric Ligand-Gated Ion Channel ELIC.
[So] Source:Structure;25(1):180-187, 2017 Jan 03.
[Is] ISSN:1878-4186
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The structural basis for alcohol modulation of neuronal pentameric ligand-gated ion channels (pLGICs) remains elusive. We determined an inhibitory mechanism of alcohol on the pLGIC Erwinia chrysanthemi (ELIC) through direct binding to the pore. X-ray structures of ELIC co-crystallized with 2-bromoethanol, in both the absence and presence of agonist, reveal 2-bromoethanol binding in the pore near T237(6') and the extracellular domain (ECD) of each subunit at three different locations. Binding to the ECD does not appear to contribute to the inhibitory action of 2-bromoethanol and ethanol as indicated by the same functional responses of wild-type ELIC and mutants. In contrast, the ELIC-α1ß3GABA R chimera, replacing the ELIC transmembrane domain (TMD) with the TMD of α1ß3GABA R, is potentiated by 2-bromoethanol and ethanol. The results suggest a dominant role of the TMD in modulating alcohol effects. The X-ray structures and functional measurements support a pore-blocking mechanism for inhibitory action of short-chain alcohols.
[Mh] Termos MeSH primário: Etanol/análogos & derivados
Canais Iônicos de Abertura Ativada por Ligante/química
Canais Iônicos de Abertura Ativada por Ligante/genética
Pectobacterium chrysanthemi/enzimologia
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalografia por Raios X
Etanol/farmacologia
Seres Humanos
Canais Iônicos de Abertura Ativada por Ligante/antagonistas & inibidores
Modelos Moleculares
Mutação
Ligação Proteica
Multimerização Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligand-Gated Ion Channels); 3K9958V90M (Ethanol); Z33995S34R (ethylene bromohydrin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161206
[St] Status:MEDLINE


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[PMID]:27845033
[Au] Autor:Hénault CM; Baenziger JE
[Ad] Endereço:Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada.
[Ti] Título:Functional characterization of two prokaryotic pentameric ligand-gated ion channel chimeras - role of the GLIC transmembrane domain in proton sensing.
[So] Source:Biochim Biophys Acta;1859(2):218-227, 2017 02.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:With the long-term goal of using a chimeric approach to dissect the distinct lipid sensitivities and thermal stabilities of the pentameric ligand-gated ion channels (pLGIC), GLIC and ELIC, we constructed chimeras by cross-combining their extracellular (ECD) and transmembrane (TMD) domains. As expected, the chimera formed between GLIC-ECD and ELIC-TMD (GE) responded to protons, the agonist for GLIC, but not cysteamine, the agonist for ELIC, although GE exhibited a 25-fold decrease in proton-sensitivity relative to wild type. The chimera formed between ELIC-ECD and the GLIC-TMD (EG) was usually toxic, unless it contained a pore-lining Ile9'Ala gain-of-function mutation. No significant improvements in expression/toxicity were observed with extensive loop substitutions at the ECD/TMD interface. Surprisingly, oocytes expressing EG-I9'A responded to both the ELIC agonist, cysteamine and the GLIC agonist, protons - the latter at pH values ≤4.0. The cysteamine- and proton-induced currents in EG-I9'A were inhibited by the GLIC TMD pore blocker, amantadine. The cysteamine-induced response of EG-I9'A was also inhibited by protons at pH values down to 4.5, but potentiated at lower pH values. Proton-induced gating at low pH was not abolished by mutation of an intramembrane histidine residue previously implicated in GLIC TMD function. We show that the TMD plays a major role governing the thermal stability of a pLGIC, and identify three distinct mechanisms by which agonists and protons influence the gating of the EG chimera. A structural basis for the impaired function of GE is suggested.
[Mh] Termos MeSH primário: Canais Iônicos de Abertura Ativada por Ligante/metabolismo
Células Procarióticas/metabolismo
[Mh] Termos MeSH secundário: Animais
Quimera/metabolismo
Cristalografia por Raios X/métodos
Cisteamina/metabolismo
Histidina/metabolismo
Ativação do Canal Iônico/fisiologia
Ligantes
Modelos Moleculares
Mutação/genética
Oócitos/metabolismo
Domínios Proteicos/fisiologia
Prótons
Xenopus laevis/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligand-Gated Ion Channels); 0 (Ligands); 0 (Protons); 4QD397987E (Histidine); 5UX2SD1KE2 (Cysteamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161116
[St] Status:MEDLINE


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[PMID]:27764665
[Au] Autor:Valbuena S; Lerma J
[Ad] Endereço:Instituto de Neurociencias CSIC-UMH, 03550 San Juan de Alicante, Spain.
[Ti] Título:Non-canonical Signaling, the Hidden Life of Ligand-Gated Ion Channels.
[So] Source:Neuron;92(2):316-329, 2016 Oct 19.
[Is] ISSN:1097-4199
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neurotransmitter receptors are responsible for the transfer of information across the synapse. While ionotropic receptors form ion channels and mediate rapid membrane depolarization, so-called metabotropic receptors exert their action though slower, less direct intracellular signaling pathways. Glutamate, GABA, and acetylcholine can activate both ionotropic and metabotropic receptors, yet the distinction between these "canonical" signaling systems has become less clear since ionotropic receptors were proposed to also activate second messenger systems, defining a "non-canonical" signaling pathway. How these alternative pathways affect neuronal circuit activity is not well understood, and their influence could be more significant than previously anticipated. In this review, we examine the evidence available that supports the existence of parallel and unsuspected signaling pathways used by ionotropic neurotransmitter receptors.
[Mh] Termos MeSH primário: Canais Iônicos de Abertura Ativada por Ligante/metabolismo
Neurônios/metabolismo
Neurotransmissores/metabolismo
Sistemas do Segundo Mensageiro
Sinapses/metabolismo
[Mh] Termos MeSH secundário: Acetilcolina/metabolismo
Ácido Glutâmico/metabolismo
Seres Humanos
Vias Neurais
Receptores de GABA-A/metabolismo
Receptores Ionotrópicos de Glutamato/metabolismo
Receptores Nicotínicos/metabolismo
Transmissão Sináptica
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Ligand-Gated Ion Channels); 0 (Neurotransmitter Agents); 0 (Receptors, GABA-A); 0 (Receptors, Ionotropic Glutamate); 0 (Receptors, Nicotinic); 3KX376GY7L (Glutamic Acid); 56-12-2 (gamma-Aminobutyric Acid); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE


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[PMID]:27677804
[Au] Autor:Powell AD; Grafton G; Roberts A; Larkin S; O'Neill N; Palandri J; Otvos R; Cooper AJ; Ulens C; Barnes NM
[Ad] Endereço:Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
[Ti] Título:Novel mechanism of modulation at a ligand-gated ion channel; action of 5-Cl-indole at the 5-HT A receptor.
[So] Source:Br J Pharmacol;173(24):3467-3479, 2016 Dec.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: The 5-HT 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-HT 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-HT receptor was assessed using single cell electrophysiological recordings and [ H]-granisetron binding in HEK293 cells stably expressing the 5-HT receptor. KEY RESULTS: Cl-indole failed to evoke 5-HT A receptor-mediated responses (up to 30 µM) or display affinity for the [ H]-granisetron binding site. However, in the presence of Cl-indole, termination of 5-HT application revealed tail currents mediated via the 5-HT A receptor that were independent of the preceding 5-HT concentration but were antagonized by the 5-HT receptor antagonist, ondansetron. These tail currents were absent in the 5-HT AB receptor. Furthermore, the presence of 5-HT revealed a concentration-dependent increase in the affinity of Cl-indole for the orthosteric binding site of the human 5-HT A receptor. CONCLUSIONS AND IMPLICATIONS: Cl-indole acts as both an orthosteric agonist and an allosteric modulator, but the presence of an orthosteric agonist (e.g. 5-HT) is a prerequisite to reveal both actions. Precedent for ago-allosteric action is available, yet the essential additional presence of an orthosteric agonist is now reported for the first time. This widening of the pharmacological mechanisms to modulate LGICs may offer further therapeutic opportunities.
[Mh] Termos MeSH primário: Indóis/farmacologia
Canais Iônicos de Abertura Ativada por Ligante/metabolismo
Receptores 5-HT3 de Serotonina/metabolismo
Agonistas de Receptores 5-HT3 de Serotonina/farmacologia
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Células Cultivadas
Células HEK293
Seres Humanos
Ligantes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indoles); 0 (Ligand-Gated Ion Channels); 0 (Ligands); 0 (Receptors, Serotonin, 5-HT3); 0 (Serotonin 5-HT3 Receptor Agonists)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160929
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13638



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