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1 / 1957

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[PMID]: 28449103 [Au] Autor: Li H; Pei W; Vergarajauregui S; Zerfas PM; Raben N; Burgess SM; Puertollano R [Ad] Endereço: Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. [Ti] Título: Novel degenerative and developmental defects in a zebrafish model of mucolipidosis type IV. [So] Source: Hum Mol Genet;26(14):2701-2718, 2017 07 15. [Is] ISSN: 1460-2083 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Mucolipidosis type IV (MLIV) is a lysosomal storage disease characterized by neurologic and ophthalmologic abnormalities. There is currently no effective treatment. MLIV is caused by mutations in MCOLN1, a lysosomal cation channel from the transient receptor potential (TRP) family. In this study, we used genome editing to knockout the two mcoln1 genes present in Danio rerio (zebrafish). Our model successfully reproduced the retinal and neuromuscular defects observed in MLIV patients, indicating that this model is suitable for studying the disease pathogenesis. Importantly, our model revealed novel insights into the origins and progression of the MLIV pathology, including the contribution of autophagosome accumulation to muscle dystrophy and the role of mcoln1 in embryonic development, hair cell viability and cellular maintenance. The generation of a MLIV model in zebrafish is particularly relevant given the suitability of this organism for large-scale in vivo drug screening, thus providing unprecedented opportunities for therapeutic discovery. [Mh] Termos MeSH primário: Mucolipidoses/genética Canais de Receptores Transientes de Potencial/genética Proteínas de Peixe-Zebra/genética [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Autofagossomos/metabolismo Modelos Animais de Doenças Técnicas de Inativação de Genes Mucolipidoses/metabolismo Mucolipidoses/patologia Mutação Canais de Receptores Transientes de Potencial/metabolismo Peixe-Zebra Proteínas de Peixe-Zebra/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., INTRAMURAL [Nm] Nome de substância: 0 (MCOLN1.1 protein, zebrafish); 0 (Transient Receptor Potential Channels); 0 (Zebrafish Proteins) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180225 [Lr] Data última revisão: 180225 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE [do] DOI: 10.1093/hmg/ddx158

2 / 1957

MEDLINE

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[PMID]: 29257953 [Au] Autor: Sigg MA; Menchen T; Lee C; Johnson J; Jungnickel MK; Choksi SP; Garcia G; Busengdal H; Dougherty GW; Pennekamp P; Werner C; Rentzsch F; Florman HM; Krogan N; Wallingford JB; Omran H; Reiter JF [Ad] Endereço: Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA. [Ti] Título: Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. [So] Source: Dev Cell;43(6):744-762.e11, 2017 12 18. [Is] ISSN: 1878-1551 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cilia are organelles specialized for movement and signaling. To infer when during evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from sea urchins, sea anemones, and choanoflagellates. We identified 437 high-confidence ciliary candidate proteins conserved in mammals and discovered that Hedgehog and G-protein-coupled receptor pathways were linked to cilia before the origin of bilateria and transient receptor potential (TRP) channels before the origin of animals. We demonstrated that candidates not previously implicated in ciliary biology localized to cilia and further investigated ENKUR, a TRP channel-interacting protein identified in the cilia of all three organisms. ENKUR localizes to motile cilia and is required for patterning the left-right axis in vertebrates. Moreover, mutation of ENKUR causes situs inversus in humans. Thus, proteomic profiling of cilia from diverse eukaryotes defines a conserved ciliary proteome, reveals ancient connections to signaling, and uncovers a ciliary protein that underlies development and human disease. [Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo Proteínas de Ligação a Calmodulina/metabolismo Cílios/genética Cílios/metabolismo [Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética Animais Proteínas de Ligação a Calmodulina/genética Técnicas de Cultura de Células Coanoflagelados/metabolismo Proteínas Hedgehog/metabolismo Seres Humanos Camundongos Mutação Organelas/metabolismo Filogenia Proteômica/métodos Receptores Acoplados a Proteínas-G/metabolismo Anêmonas-do-Mar/metabolismo Ouriços-do-Mar/metabolismo Transdução de Sinais/genética Transdução de Sinais/fisiologia Canais de Receptores Transientes de Potencial/metabolismo Xenopus laevis/metabolismo Peixe-Zebra/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (Calmodulin-Binding Proteins); 0 (ENKUR protein, human); 0 (Hedgehog Proteins); 0 (Receptors, G-Protein-Coupled); 0 (Transient Receptor Potential Channels) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180210 [Lr] Data última revisão: 180210 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171220 [St] Status: MEDLINE

3 / 1957

MEDLINE

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[PMID]: 28448473 [Au] Autor: Pérez-Riesgo E; Gutiérrez LG; Ubierna D; Acedo A; Moyer MP; Núñez L; Villalobos C [Ad] Endereço: Institute of Molecular Biology and Genetics (IBGM), National Research Council (CSIC), 47003 Valladolid, Spain. epercamh@gmail.com. [Ti] Título: Transcriptomic Analysis of Calcium Remodeling in Colorectal Cancer. [So] Source: Int J Mol Sci;18(5), 2017 Apr 27. [Is] ISSN: 1422-0067 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Colorectal cancer (CRC) cells undergo the remodeling of intracellular Ca homeostasis, which contributes to cancer hallmarks such as enhanced proliferation, invasion and survival. Ca remodeling includes critical changes in store-operated Ca entry (SOCE) and Ca store content. Some changes have been investigated at the molecular level. However, since nearly 100 genes are involved in intracellular Ca transport, a comprehensive view of Ca remodeling in CRC is lacking. We have used Next Generation Sequencing (NGS) to investigate differences in expression of 77 selected gene transcripts involved in intracellular Ca transport in CRC. To this end, mRNA from normal human colonic NCM460 cells and human colon cancer HT29 cells was isolated and used as a template for transcriptomic sequencing and expression analysis using Ion Torrent technology. After data transformation and filtering, exploratory analysis revealed that both cell types were well segregated. In addition, differential gene expression using R and bioconductor packages show significant differences in expression of selected voltage-operated Ca channels and store-operated Ca entry players, transient receptor potential (TRP) channels, Ca release channels, Ca pumps, Naâ�º/Ca exchanger isoforms and genes involved in mitochondrial Ca transport. These data provide the first comprehensive transcriptomic analysis of Ca remodeling in CRC. [Mh] Termos MeSH primário: Canais de Cálcio/genética Cálcio/metabolismo Perfilação da Expressão Gênica [Mh] Termos MeSH secundário: Canais de Cálcio/metabolismo Linhagem Celular Tumoral Análise por Conglomerados Neoplasias Colorretais/genética Neoplasias Colorretais/metabolismo Neoplasias Colorretais/patologia Regulação da Expressão Gênica Células HT29 Sequenciamento de Nucleotídeos em Larga Escala Seres Humanos Análise de Componente Principal Análise de Sequência de RNA Trocador de Sódio e Cálcio/genética Trocador de Sódio e Cálcio/metabolismo Canais de Receptores Transientes de Potencial/genética Canais de Receptores Transientes de Potencial/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium Channels); 0 (Sodium-Calcium Exchanger); 0 (Transient Receptor Potential Channels); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180122 [Lr] Data última revisão: 180122 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170428 [St] Status: MEDLINE

4 / 1957

MEDLINE

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[PMID]: 28903060 [Au] Autor: Nalli M; Ortar G; Schiano Moriello A; Di Marzo V; De Petrocellis L [Ad] Endereço: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, piazzale Aldo Moro 5, 00185 Roma, Italy. Electronic address: marianna.nalli@uniroma1.it. [Ti] Título: Effects of curcumin and curcumin analogues on TRP channels. [So] Source: Fitoterapia;122:126-131, 2017 Oct. [Is] ISSN: 1873-6971 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: A series of 33 curcumin analogues was synthesized and tested on TRPA1, TRPM8, and TRPV1 channels. Twenty of them acted as good modulators of TRPA1 channels. None was able to significantly activate TRPM8 channels, while curcumin itself and six curcuminoids belonging to the 1,3-dicarbonyl and acyclic series behaved as 'true' antagonists with IC values<5µM. Only few curcuminoids were able to modulate TRPV1 channels with EC and IC values ranging from 3.4 and 6.0µM. [Mh] Termos MeSH primário: Curcumina/análogos & derivados Canais de Receptores Transientes de Potencial/efeitos dos fármacos [Mh] Termos MeSH secundário: Animais Células HEK293 Seres Humanos Estrutura Molecular Ratos Canal de Cátion TRPA1 Canais de Cátion TRPC/efeitos dos fármacos Canais de Cátion TRPM/efeitos dos fármacos Canais de Cátion TRPV/efeitos dos fármacos [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (TRPA1 Cation Channel); 0 (TRPC Cation Channels); 0 (TRPM Cation Channels); 0 (TRPV Cation Channels); 0 (TRPV1 protein, human); 0 (Transient Receptor Potential Channels); 0 (Trpa1 protein, rat); 0 (Trpm8 protein, rat); IT942ZTH98 (Curcumin) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170914 [St] Status: MEDLINE

5 / 1957

MEDLINE

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[PMID]: 28779020 [Au] Autor: Dayam RM; Sun CX; Choy CH; Mancuso G; Glogauer M; Botelho RJ [Ad] Endereço: Department of Chemistry and Biology, Ryerson University, Toronto, Ontario M5B 2K3, Canada. [Ti] Título: The Lipid Kinase PIKfyve Coordinates the Neutrophil Immune Response through the Activation of the Rac GTPase. [So] Source: J Immunol;199(6):2096-2105, 2017 Sep 15. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Neutrophils rapidly arrive at an infection site because of their unparalleled chemotactic ability, after which they unleash numerous attacks on pathogens through degranulation and reactive oxygen species (ROS) production, as well as by phagocytosis, which sequesters pathogens within phagosomes. Phagosomes then fuse with lysosomes and granules to kill the enclosed pathogens. A complex signaling network composed of kinases, GTPases, and lipids, such as phosphoinositides, helps to coordinate all of these processes. There are seven species of phosphoinositides that are interconverted by lipid kinases and phosphatases. PIKfyve is a lipid kinase that generates phosphatidylinositol-3,5-bisphosphate and, directly or indirectly, phosphatidylinositol-5-phosphate [PtdIns(5)P]. PIKfyve inactivation causes massive lysosome swelling, disrupts membrane recycling, and, in macrophages, blocks phagosome maturation. In this study, we explored for the first time, to our knowledge, the role of PIKfyve in human and mouse neutrophils. We show that PIKfyve inhibition in neutrophils does not affect granule morphology or degranulation, but it causes LAMP1 lysosomes to engorge. Additionally, PIKfyve inactivation blocks phagosome-lysosome fusion in a manner that can be rescued, in part, with Ca ionophores or agonists of TRPML1, a lysosomal Ca channel. Strikingly, PIKfyve is necessary for chemotaxis, ROS production, and stimulation of the Rac GTPases, which control chemotaxis and ROS. This is consistent with observations in nonleukocytes that showed that PIKfyve and PtdIns(5)P control Rac and cell migration. Overall, we demonstrate that PIKfyve has a robust role in neutrophils and propose a model in which PIKfyve modulates phagosome maturation through phosphatidylinositol-3,5-bisphosphate-dependent activation of TRPML1, whereas chemotaxis and ROS are regulated by PtdIns(5)P-dependent activation of Rac. [Mh] Termos MeSH primário: Lisossomos/metabolismo Neutrófilos/imunologia Fosfatidilinositol 3-Quinases/metabolismo [Mh] Termos MeSH secundário: Aminopiridinas/farmacologia Animais Degranulação Celular Células Cultivadas Quimiotaxia GTP Fosfo-Hidrolases/metabolismo Compostos Heterocíclicos com 3 Anéis/farmacologia Seres Humanos Proteína 1 de Membrana Associada ao Lisossomo/metabolismo Fusão de Membrana Camundongos Camundongos Endogâmicos Morfolinas/farmacologia Fagocitose Fagossomos/metabolismo Fosfatidilinositol 3-Quinases/antagonistas & inibidores Fosfatos de Fosfatidilinositol/metabolismo Espécies Reativas de Oxigênio/metabolismo Canais de Receptores Transientes de Potencial/metabolismo Triazinas/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide); 0 (Aminopyridines); 0 (Heterocyclic Compounds, 3-Ring); 0 (Lysosomal-Associated Membrane Protein 1); 0 (Mcoln1 protein, mouse); 0 (Morpholines); 0 (Phosphatidylinositol Phosphates); 0 (Reactive Oxygen Species); 0 (Transient Receptor Potential Channels); 0 (Triazines); 0 (phosphatidylinositol 5-phosphate); 5G3P5OK11S (apilimod mesylate); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (Pikfyve protein, mouse); EC 3.6.1.- (GTP Phosphohydrolases) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171010 [Lr] Data última revisão: 171010 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170806 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1601466

6 / 1957

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[PMID]: 28732201 [Au] Autor: Chen CC; Butz ES; Chao YK; Grishchuk Y; Becker L; Heller S; Slaugenhaupt SA; Biel M; Wahl-Schott C; Grimm C [Ad] Endereço: Department of Pharmacy, Center for Drug Research and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, 81377 Munich, Germany. [Ti] Título: Small Molecules for Early Endosome-Specific Patch Clamping. [So] Source: Cell Chem Biol;24(7):907-916.e4, 2017 Jul 20. [Is] ISSN: 2451-9456 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: To resolve the subcellular distribution of endolysosomal ion channels, we have established a novel experimental approach to selectively patch clamp Rab5 positive early endosomes (EE) versus Rab7/LAMP1-positive late endosomes/lysosomes (LE/LY). To functionally characterize ion channels in endolysosomal membranes with the patch-clamp technique, it is important to develop techniques to selectively enlarge the respective organelles. We found here that two small molecules, wortmannin and latrunculin B, enlarge Rab5-positive EE when combined but not Rab7-, LAMP1-, or Rab11 (RE)-positive vesicles. The two compounds act rapidly, specifically, and are readily applicable in contrast to genetic approaches or previously used compounds such as vacuolin, which enlarges EE, RE, and LE/LY. We apply this approach here to measure currents mediated by TRPML channels, in particular TRPML3, which we found to be functionally active in both EE and LE/LY in overexpressing cells as well as in endogenously expressing CD11b+ lung-tissue macrophages. [Mh] Termos MeSH primário: Potenciais de Ação/efeitos dos fármacos Androstadienos/farmacologia Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia Endossomos/metabolismo Tiazolidinas/farmacologia [Mh] Termos MeSH secundário: Aminopiridinas/farmacologia Antígeno CD11b/metabolismo Endossomos/efeitos dos fármacos Células HEK293 Compostos Heterocíclicos com 3 Anéis/farmacologia Seres Humanos Pulmão/citologia Pulmão/metabolismo Proteína 1 de Membrana Associada ao Lisossomo/metabolismo Lisossomos/efeitos dos fármacos Lisossomos/metabolismo Macrófagos/citologia Macrófagos/efeitos dos fármacos Macrófagos/metabolismo Macrófagos Peritoneais/citologia Macrófagos Peritoneais/efeitos dos fármacos Macrófagos Peritoneais/metabolismo Técnicas de Patch-Clamp Canais de Receptores Transientes de Potencial/genética Canais de Receptores Transientes de Potencial/metabolismo Proteínas rab de Ligação ao GTP/metabolismo Proteínas rab5 de Ligação ao GTP/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (6-amino-N-(3-(4-(4-morpholinyl)pyrido(3',2'-4,5)furo(3,2-d)pyrimidin-2-yl)phenyl)-3-pyridinecarboxamide); 0 (Aminopyridines); 0 (Androstadienes); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (CD11b Antigen); 0 (Heterocyclic Compounds, 3-Ring); 0 (Lysosomal-Associated Membrane Protein 1); 0 (MCOLN1 protein, human); 0 (MCOLN3 protein, human); 0 (Thiazolidines); 0 (Transient Receptor Potential Channels); 152989-05-4 (rab7 protein); EC 3.6.1.- (rab11 protein); EC 3.6.5.2 (rab GTP-Binding Proteins); EC 3.6.5.2 (rab5 GTP-Binding Proteins); LW7U308U7U (latrunculin B); XVA4O219QW (wortmannin) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170722 [St] Status: MEDLINE

7 / 1957

MEDLINE

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[PMID]: 28658211 [Au] Autor: Jin P; Bulkley D; Guo Y; Zhang W; Guo Z; Huynh W; Wu S; Meltzer S; Cheng T; Jan LY; Jan YN; Cheng Y [Ad] Endereço: Department of Physiology, University of California, San Francisco, California 94158, USA. [Ti] Título: Electron cryo-microscopy structure of the mechanotransduction channel NOMPC. [So] Source: Nature;547(7661):118-122, 2017 07 06. [Is] ISSN: 1476-4687 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Mechanosensory transduction for senses such as proprioception, touch, balance, acceleration, hearing and pain relies on mechanotransduction channels, which convert mechanical stimuli into electrical signals in specialized sensory cells. How force gates mechanotransduction channels is a central question in the field, for which there are two major models. One is the membrane-tension model: force applied to the membrane generates a change in membrane tension that is sufficient to gate the channel, as in the bacterial MscL channel and certain eukaryotic potassium channels. The other is the tether model: force is transmitted via a tether to gate the channel. The transient receptor potential (TRP) channel NOMPC is important for mechanosensation-related behaviours such as locomotion, touch and sound sensation across different species including Caenorhabditis elegans, Drosophila and zebrafish. NOMPC is the founding member of the TRPN subfamily, and is thought to be gated by tethering of its ankyrin repeat domain to microtubules of the cytoskeleton. Thus, a goal of studying NOMPC is to reveal the underlying mechanism of force-induced gating, which could serve as a paradigm of the tether model. NOMPC fulfils all the criteria that apply to mechanotransduction channels and has 29 ankyrin repeats, the largest number among TRP channels. A key question is how the long ankyrin repeat domain is organized as a tether that can trigger channel gating. Here we present a de novo atomic structure of Drosophila NOMPC determined by single-particle electron cryo-microscopy. Structural analysis suggests that the ankyrin repeat domain of NOMPC resembles a helical spring, suggesting its role of linking mechanical displacement of the cytoskeleton to the opening of the channel. The NOMPC architecture underscores the basis of translating mechanical force into an electrical signal within a cell. [Mh] Termos MeSH primário: Microscopia Crioeletrônica Proteínas de Drosophila/ultraestrutura Canais de Receptores Transientes de Potencial/ultraestrutura [Mh] Termos MeSH secundário: Animais Proteínas de Drosophila/química Proteínas de Drosophila/metabolismo Drosophila melanogaster Lipídeos Mecanotransdução Celular Modelos Moleculares Movimento Domínios Proteicos Canais de Receptores Transientes de Potencial/química Canais de Receptores Transientes de Potencial/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Drosophila Proteins); 0 (Lipids); 0 (NOMPC protein, Drosophila); 0 (Transient Receptor Potential Channels) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171113 [Lr] Data última revisão: 171113 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170629 [St] Status: MEDLINE [do] DOI: 10.1038/nature22981

8 / 1957

MEDLINE

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[PMID]: 28657737 [Au] Autor: Mathie K; Lainer J; Spreng S; Dawid C; Andersson DA; Bevan S; Hofmann T [Ad] Endereço: Chair of Food Chemistry and Molecular Sensory Science, Technische Universität München , Lise-Meitner-Straße 34, D-85350 Freising, Germany , and. [Ti] Título: Structure-Pungency Relationships and TRP Channel Activation of Drimane Sesquiterpenes in Tasmanian Pepper (Tasmannia lanceolata). [So] Source: J Agric Food Chem;65(28):5700-5712, 2017 Jul 19. [Is] ISSN: 1520-5118 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Sensory-guided fractionation of extracts of Tasmanian pepper berries revealed 20 drimane sesquiterpens, among which polygodial, warburganal, and 1ß-acetoxy-9-deoxy-isomuzigadial exhibited the lowest pungency threshold concentrations on the tongue surface (0.6-2.8 nmol/cm ) and elicited a dose-dependent calcium influx into mTRPA1 expressing CHO cells with the lowest EC values (4.5 ± 1.0 to 16.7 ± 7.5 µmol/L) and a good correlation to oral pungency thresholds (R = 0.986, linear regression). Calcium imaging assays demonstrated these chemosensates to induce a calcium influx into cultured trigeminal neurons prepared from wildtype (TRPA1 ) mice, whereas no calcium influx was observed in neurons from TRPA1 knockout mice (TRPA1 ), thus confirming the α,ß-unsaturated 1,4-dialdehyde structure to be the required structural motif for a low oral puncency thresholds and activation of the Transient Receptor Potential Channel A1 (TRPA1). Time-resolved NMR experiments confirmed the pungency mediating mechanism for electrophilic drimane sesquiterpene dialdehydes to be different from that found for other electrophilic pungent agents like isothiocyanates, which have been shown to undergo a covalent binding with cysteine residues in TRPA1. Instead, the high-impact chemosensates polygodial, warburganal, and 1ß-acetoxy-9-deoxy-isomuzigadial showed immediate reactivity with the ε-amino group of lysine side chains to give pyrrole-type conjugates, thus showing evidence for TRPA1 activation by covalent lysine modification. [Mh] Termos MeSH primário: Canais de Cálcio/metabolismo Proteínas do Tecido Nervoso/metabolismo Extratos Vegetais/química Sesquiterpenos/química Paladar Canais de Receptores Transientes de Potencial/metabolismo Winteraceae/química [Mh] Termos MeSH secundário: Adulto Animais Células CHO Cálcio/metabolismo Canais de Cálcio/genética Cricetulus Feminino Seres Humanos Masculino Camundongos Camundongos Knockout Proteínas do Tecido Nervoso/genética Extratos Vegetais/metabolismo Sesquiterpenos/metabolismo Canal de Cátion TRPA1 Canais de Receptores Transientes de Potencial/genética Winteraceae/metabolismo Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium Channels); 0 (Nerve Tissue Proteins); 0 (Plant Extracts); 0 (Sesquiterpenes); 0 (TRPA1 Cation Channel); 0 (TRPA1 protein, human); 0 (Transient Receptor Potential Channels); 0 (Trpa1 protein, mouse); 0 (drimane); SY7Q814VUP (Calcium) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170629 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jafc.7b02356

9 / 1957

MEDLINE

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[PMID]: 28648659 [Au] Autor: Bellono NW; Bayrer JR; Leitch DB; Castro J; Zhang C; O'Donnell TA; Brierley SM; Ingraham HA; Julius D [Ad] Endereço: Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA. [Ti] Título: Enterochromaffin Cells Are Gut Chemosensors that Couple to Sensory Neural Pathways. [So] Source: Cell;170(1):185-198.e16, 2017 Jun 29. [Is] ISSN: 1097-4172 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Dietary, microbial, and inflammatory factors modulate the gut-brain axis and influence physiological processes ranging from metabolism to cognition. The gut epithelium is a principal site for detecting such agents, but precisely how it communicates with neural elements is poorly understood. Serotonergic enterochromaffin (EC) cells are proposed to fulfill this role by acting as chemosensors, but understanding how these rare and unique cell types transduce chemosensory information to the nervous system has been hampered by their paucity and inaccessibility to single-cell measurements. Here, we circumvent this limitation by exploiting cultured intestinal organoids together with single-cell measurements to elucidate intrinsic biophysical, pharmacological, and genetic properties of EC cells. We show that EC cells express specific chemosensory receptors, are electrically excitable, and modulate serotonin-sensitive primary afferent nerve fibers via synaptic connections, enabling them to detect and transduce environmental, metabolic, and homeostatic information from the gut directly to the nervous system. [Mh] Termos MeSH primário: Células Quimiorreceptoras/metabolismo Células Enterocromafins/metabolismo Trato Gastrointestinal/citologia Vias Neurais [Mh] Termos MeSH secundário: Sequência de Aminoácidos Animais Sequência de Bases Canais de Cálcio/metabolismo Catecolaminas/metabolismo Perfilação da Expressão Gênica Seres Humanos Síndrome do Intestino Irritável/patologia Camundongos Fibras Nervosas/metabolismo Proteínas do Tecido Nervoso/metabolismo Receptores Odorantes/metabolismo Receptores 5-HT3 de Serotonina/metabolismo Serotonina/metabolismo Transdução de Sinais Sinapses/metabolismo Canal de Cátion TRPA1 Canais de Receptores Transientes de Potencial/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Calcium Channels); 0 (Catecholamines); 0 (Nerve Tissue Proteins); 0 (Olfr558 protein, mouse); 0 (Receptors, Odorant); 0 (Receptors, Serotonin, 5-HT3); 0 (TRPA1 Cation Channel); 0 (TRPA1 protein, human); 0 (Transient Receptor Potential Channels); 333DO1RDJY (Serotonin) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170627 [St] Status: MEDLINE

10 / 1957

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[PMID]: 28644897 [Au] Autor: Sinharoy P; Bratz IN; Sinha S; Showalter LE; Andrei SR; Damron DS [Ad] Endereço: Department of Anesthesia, Perioperative and Pain Medicine, Stanford School of Medicine, Stanford, California, United States of America. [Ti] Título: TRPA1 and TRPV1 contribute to propofol-mediated antagonism of U46619-induced constriction in murine coronary arteries. [So] Source: PLoS One;12(6):e0180106, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: Transient receptor potential (TRP) ion channels have emerged as key components contributing to vasoreactivity. Propofol, an anesthetic is associated with adverse side effects including hypotension and acute pain upon infusion. Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofol-induced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs. METHODS: Hearts were excised from anesthetized mice and coronary arterioles were dissected from control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). Isolated microvessels were cannulated and secured in a temperature-controlled chamber and allowed to equilibrate for 1 hr. Vasoreactivity studies were performed in microvessels pre-constricted with U46619 to assess the dose-dependent relaxation effects of propofol on coronary microvascular tone. RESULTS: Propofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV-/- mice. Furthermore, NOS inhibition with L-NAME or endothelium denuding abolished the proporfol-induced depressor response in pre-constricted vessels obtained from all mice. In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild-type mice and to a lesser extent in vessels obtained from TRPV1-/-, mice with no effect in vessels obtained from TRPA1-/- or TRPAV-/- mice. CONCLUSIONS: TRPA1 and TRPV1 appear to contribute to the propofol-mediated antagonism of U46619-induced constriction in murine coronary microvessels that involves activation of NOS and BKCa. [Mh] Termos MeSH primário: Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/antagonistas & inibidores Vasos Coronários/efeitos dos fármacos Propofol/farmacologia Canais de Cátion TRPV/metabolismo Canais de Receptores Transientes de Potencial/metabolismo Vasodilatadores/farmacologia [Mh] Termos MeSH secundário: Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia Animais Células Cultivadas Vasos Coronários/metabolismo Células Endoteliais/efeitos dos fármacos Células Endoteliais/metabolismo Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo Masculino Camundongos Endogâmicos C57BL Camundongos Knockout Microvasos/efeitos dos fármacos Microvasos/metabolismo Óxido Nítrico Sintase Tipo III/metabolismo Canal de Cátion TRPA1 Canais de Cátion TRPV/genética Canais de Receptores Transientes de Potencial/genética Vasoconstritores/antagonistas & inibidores Vasoconstritores/farmacologia Vasodilatação/efeitos dos fármacos Vasodilatação/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (BKCa protein, mouse); 0 (Large-Conductance Calcium-Activated Potassium Channel alpha Subunits); 0 (TRPA1 Cation Channel); 0 (TRPV Cation Channels); 0 (TRPV1 protein, mouse); 0 (Transient Receptor Potential Channels); 0 (Trpa1 protein, mouse); 0 (Vasoconstrictor Agents); 0 (Vasodilator Agents); 76898-47-0 (15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.14.13.39 (Nos3 protein, mouse); YI7VU623SF (Propofol) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170624 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0180106

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