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Tmem16a

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https://www.readbyqxmd.com/read/28493701/substituted-2-acylamino-cycloalkylthiophene-3-carboxylic-acid-arylamides-as-inhibitors-of-the-calcium-activated-chloride-channel-transmembrane-protein-16a-tmem16a
#1
Eric C Truong, Puay-Wah Phuan, Amanda L Reggi, Loretta Ferrera, Luis J V Galietta, Sarah E Levy, Alannah C Moises, Onur Cil, Elena Diez-Cecilia, Sujin Lee, Alan S Verkman, Marc O Anderson
Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report by screening the discovery of 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A, and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa)...
May 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28488084/loop-diuretics-diminish-hemolysis-induced-by-%C3%AE-hemolysin-from-escherichia-coli
#2
Carl Martin Söderström, Steen K Fagerberg, Mette B Brogaard, Jens Leipziger, Marianne Skals, Helle A Praetorius
Uropathogenic Escherichia coli often produce the virulence factor α-hemolysin (HlyA), and the more severe the infection, the likelier it is to isolate HlyA-producing E. coli from patients. HlyA forms pores upon receptor-independent insertion of the toxin into biological membranes and it has been substantiated that HlyA-induced hemolysis is amplified by toxin-induced ATP release and activation of P2X receptors. Thus, hemolysis inflicted by HlyA is a protracted process involving signal transduction. It consists of early, marked cell shrinkage followed by swelling and eventually lysis...
May 9, 2017: Journal of Membrane Biology
https://www.readbyqxmd.com/read/28452066/inhibition-of-tmem16a-calcium-activated-chloride-channels-by-natural-flavonoids-contributes-to-flavonoid-anticancer-effects
#3
Xuan Zhang, Honglin Li, Huiran Zhang, Yani Liu, Lifang Huo, Zhanfeng Jia, Yucong Xue, Xiaorun Sun, Wei Zhang
BACKGROUND AND PURPOSE: Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective, and anticancer effects. Transmembrane member 16A (TMEM16A) encoded Ca(2+) -activated Cl(-) channels play a variety of physiological roles in many organs and tissues. Overexpression of TMEM16A is also believed to be associated with cancer progression. Therefore, inhibition of TMEM16A may be a potential target for cancer therapy...
April 27, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28420732/modulation-of-tmem16a-channel-activity-by-the-von-willebrand-factor-type-a-vwa-domain-of-the-calcium-activated-chloride-channel-regulator-1-clca1
#4
Monica Sala-Rabanal, Zeynep Yurtsever, Kayla N Berry, Colin G Nichols, Tom J Brett
Calcium-activated chloride channels (CaCCs) are key players in transepithelial ion transport and fluid secretion, smooth muscle constriction, neuronal excitability, and cell proliferation. The CaCC regulator 1 (CLCA1) modulates the activity of the CaCC TMEM16A/Anoctamin 1 (ANO1) by directly engaging the channel at the cell surface, but the exact mechanism is unknown. Here, we demonstrate that the von Willebrand factor type A (VWA) domain within the cleaved CLCA1 N-terminal fragment is necessary and sufficient for this interaction...
April 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28394258/large-scale-genome-wide-analysis-identifies-genetic-variants-associated-with-cardiac-structure-and-function
#5
Philipp S Wild, Janine F Felix, Arne Schillert, Alexander Teumer, Ming-Huei Chen, Maarten J G Leening, Uwe Völker, Vera Großmann, Jennifer A Brody, Marguerite R Irvin, Sanjiv J Shah, Setia Pramana, Wolfgang Lieb, Reinhold Schmidt, Alice V Stanton, Dörthe Malzahn, Albert Vernon Smith, Johan Sundström, Cosetta Minelli, Daniela Ruggiero, Leo-Pekka Lyytikäinen, Daniel Tiller, J Gustav Smith, Claire Monnereau, Marco R Di Tullio, Solomon K Musani, Alanna C Morrison, Tune H Pers, Michael Morley, Marcus E Kleber, Jayashri Aragam, Emelia J Benjamin, Joshua C Bis, Egbert Bisping, Ulrich Broeckel, Susan Cheng, Jaap W Deckers, Fabiola Del Greco M, Frank Edelmann, Myriam Fornage, Lude Franke, Nele Friedrich, Tamara B Harris, Edith Hofer, Albert Hofman, Jie Huang, Alun D Hughes, Mika Kähönen, Knhi Investigators, Jochen Kruppa, Karl J Lackner, Lars Lannfelt, Rafael Laskowski, Lenore J Launer, Margrét Leosdottir, Honghuang Lin, Cecilia M Lindgren, Christina Loley, Calum A MacRae, Deborah Mascalzoni, Jamil Mayet, Daniel Medenwald, Andrew P Morris, Christian Müller, Martina Müller-Nurasyid, Stefania Nappo, Peter M Nilsson, Sebastian Nuding, Teresa Nutile, Annette Peters, Arne Pfeufer, Diana Pietzner, Peter P Pramstaller, Olli T Raitakari, Kenneth M Rice, Fernando Rivadeneira, Jerome I Rotter, Saku T Ruohonen, Ralph L Sacco, Tandaw E Samdarshi, Helena Schmidt, Andrew S P Sharp, Denis C Shields, Rossella Sorice, Nona Sotoodehnia, Bruno H Stricker, Praveen Surendran, Simon Thom, Anna M Töglhofer, André G Uitterlinden, Rolf Wachter, Henry Völzke, Andreas Ziegler, Thomas Münzel, Winfried März, Thomas P Cappola, Joel N Hirschhorn, Gary F Mitchell, Nicholas L Smith, Ervin R Fox, Nicole D Dueker, Vincent W V Jaddoe, Olle Melander, Martin Russ, Terho Lehtimäki, Marina Ciullo, Andrew A Hicks, Lars Lind, Vilmundur Gudnason, Burkert Pieske, Anthony J Barron, Robert Zweiker, Heribert Schunkert, Erik Ingelsson, Kiang Liu, Donna K Arnett, Bruce M Psaty, Stefan Blankenberg, Martin G Larson, Stephan B Felix, Oscar H Franco, Tanja Zeller, Ramachandran S Vasan, Marcus Dörr
BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function...
May 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28392397/tmem16a-exacerbates-renal-injury-by-activating-p38-jnk-signaling-pathway-to-promote-podocyte-apoptosis-in-diabetic-nephropathy-mice
#6
Huan Lian, Yi Cheng, Xiaoyan Wu
Diabetic nephropathy (DN) is one of the most common microvascular complication of diabetes mellitus (DM) as well as the main reason resulting in chronic renal failure. Transmembrane protein 16A (TMEM16A) plays an important role in multiple physiological actions. Here we found that it was up-regulated in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) amplification, Western blot detection, Periodic Acid Schiff (PAS) staining and immunohistochemical analysis confirmed that TMEM16A deficiency alleviated renal injury in diabetic mice and TMEM16A knockout diabetic mice were protected from the HFD-induced reduction in Nephrin expression...
April 6, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28336549/eavk-segment-c-sequence-confers-ca-2-dependent-changes-to-the-kinetics-of-full-length-human-ano1
#7
Peter R Strege, Simon J Gibbons, Amelia Mazzone, Cheryl E Bernard, Arthur Beyder, Gianrico Farrugia
Anoctamin1 (Ano1, TMEM16A) is a calcium-activated chloride channel specifically expressed in interstitial cells of Cajal (ICC) of the gastrointestinal (GI) tract muscularis propria. Ano1 is necessary for normal electrical slow waves and ICC proliferation. The full length human Ano1 sequence includes an additional exon, exon "0," at the N-terminus. Ano1 with exon "0" (Ano1(0)) had a lower EC50 for intracellular calcium ([Ca(2+)]i) and faster chloride current (ICl) kinetics. The Ano1 alternative splice variant with segment "c" encoding exon 13 expresses on the first intracellular loop four additional amino acid residues, EAVK, which alter ICl at low [Ca(2+)]i Exon 13 is expressed in 75-100% of Ano1 transcripts in most human tissues but only 25% in human stomach...
March 23, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28320851/tmem16a-contributes-to-endothelial-dysfunction-by-facilitating-nox2-nadph-oxidase-derived-reactive-oxygen-species-generation-in-hypertension
#8
Ming-Ming Ma, Min Gao, Kai-Min Guo, Mi Wang, Xiang-Yu Li, Xue-Lin Zeng, Lu Sun, Xiao-Fei Lv, Yan-Hua Du, Guan-Lei Wang, Jia-Guo Zhou, Yong-Yuan Guan
Ca(2+)-activated Cl(-) channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism. Reverse transcription-polymerase chain reaction, Western blotting, coimmunoprecipitation, confocal imaging, patch-clamp recordings, and TMEM16A endothelial-specific transgenic and knockout mice were used...
May 2017: Hypertension
https://www.readbyqxmd.com/read/28217875/mechanisms-of-pruritogen-induced-activation-of-itch-nerves-in-isolated-mouse-skin
#9
F Ru, H Sun, D Jurcakova, R A Herbstsomer, J Meixong, X Dong, B J Undem
Chloroquine (CQ) and histamine are pruritogens commonly used to study itch in the mouse. A novel skin-nerve preparation was used to evaluate chloroquine (CQ)- and histamine- induced activation of afferent nerves in the dorsal thoracic skin of the mouse. All CQ sensitive nerves were C-fibres, and were also sensitive to histamine. The response to CQ, but not histamine, was largely absent in mrgpr cluster Δ -/- mice supporting the hypothesis that CQ evokes itch largely via stimulation of MrgprA3 receptors. The CQ-induced action potential discharge was largely absent in phospholipase Cβ3 knockout animals...
February 19, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28193228/microrna-381-inhibits-the-metastasis-of-gastric-cancer-by-targeting-tmem16a-expression
#10
Qinghua Cao, Fang Liu, Kaiyuan Ji, Ni Liu, Yuan He, Wenhui Zhang, Liantang Wang
BACKGROUND: MicroRNA-381 (miR-381) has been reported to play suppressive or promoting roles in different malignancies. However, the expression level, biological function, and underlying mechanisms of miR-381 in gastric cancer remain poorly understood. Our previous study indicated that transmembrane protein 16A (TMEM16A) contributed to migration and invasion of gastric cancer and predicted poor prognosis. In this study, we found that miR-381 inhibited the metastasis of gastric cancer through targeting TMEM16A expression...
February 13, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28183802/differential-effects-of-anoctamins-on-intracellular-calcium-signals
#11
Inês Cabrita, Roberta Benedetto, Ana Fonseca, Podchanart Wanitchakool, Lalida Sirianant, Boris V Skryabin, Laura K Schenk, Hermann Pavenstädt, Rainer Schreiber, Karl Kunzelmann
The Ca(2+) activated Cl(-) channel TMEM16A [anoctamin (ANO)1] is homologous to yeast Ist2 and has been shown to tether the cortical endoplasmic reticulum (ER) to the plasma membrane. We therefore examined whether ANO1 and other members of the ANO family affect intracellular Ca(2+) ([Ca(2+)]i) signals. It is shown that expression of ANO1 augments Ca(2+) store release upon stimulation of GPCRs, whereas knockdown of ANO1, or lack of Ano1 expression in Ano1(-/-) animals as shown in an earlier report, inhibits Ca(2+) release...
February 9, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28177558/tmem16a-ano1-suppression-improves-response-to-antibody-mediated-targeted-therapy-of-egfr-and-her2-erbb2
#12
Sucheta Kulkarni, Anke Bill, Neal R Godse, Nayel I Khan, Jason I Kass, Kevin Steehler, Carolyn Kemp, Kara Davis, Carol A Bertrand, Avani R Vyas, Douglas E Holt, Jennifer R Grandis, L Alex Gaither, Umamaheswar Duvvuri
TMEM16A, a Ca(2+) -activated Cl(-) channel, contributes to tumor growth in breast cancer and head and neck squamous cell carcinoma (HNSCC). Here, we investigated whether TMEM16A influences the response to EGFR/HER family-targeting biological therapies. Inhibition of TMEM16A Cl(-) channel activity in breast cancer cells with HER2 amplification induced a loss of viability. Cells resistant to trastuzumab, a monoclonal antibody targeting HER2, showed an increase in TMEM16A expression and heightened sensitivity to Cl(-) channel inhibition...
June 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28124133/ginsenoside-rb1-a-novel-activator-of-the-tmem16a-chloride-channel-augments-the-contraction-of-guinea-pig-ileum
#13
Shuai Guo, Yafei Chen, Chunli Pang, Xuzhao Wang, Jinlong Qi, Li Mo, Hailin Zhang, Hailong An, Yong Zhan
Calcium-activated chloride channels (CaCCs) play important roles in many physiological processes, and the molecular basis of CaCCs has been identified as TMEM16A in many cell types. It is well established that TMEM16A is a drug target in many diseases, including cystic fibrosis, hypertension, asthma, and various tumors. Therefore, identifying potent and specific modulators of the TMEM16A channel is crucial. In this study, we identified the first natural activator of TMEM16A from traditional Chinese medicine and explored its mechanism...
January 25, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28122116/chloride-goes-through-tmem16a-channels-with-permission-from-ca-2-and-encouragement-from-protons
#14
Francisco V Sepúlveda
No abstract text is available yet for this article.
March 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28109183/chloride-ion-transport-and-overexpression-of-tmem16a-in-a-guinea-pig-asthma-model
#15
M Kondo, M Tsuji, K Hara, K Arimura, O Yagi, E Tagaya, K Takeyama, J Tamaoki
BACKGROUND: TMEM16A, a Ca-activated Cl channel, regulates various physiological functions such as mucin secretion. However, the role of TMEM16A in hyper-secretion in asthma is not fully understood. OBJECTIVE: The aim of this study is to evaluate Cl ion transport via TMEM16A and determine the localization of TMEM16A in a guinea-pig asthma model. METHODS: Guinea-pigs were sensitized with ovalbumin (OVA) i.p. on Days 1 and 8. On Day 22, we assessed OVA challenge-induced Cl ion transport in the sensitized tracheas ex vivo in an Ussing chamber, compared with the non-sensitized tracheas...
January 21, 2017: Clinical and Experimental Allergy: Journal of the British Society for Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28046119/permeation-mechanisms-in-the-tmem16b-calcium-activated-chloride-channels
#16
Simone Pifferi
TMEM16A and TMEM16B encode for Ca2+-activated Cl- channels (CaCC) and are expressed in many cell types and play a relevant role in many physiological processes. Here, I performed a site-directed mutagenesis study to understand the molecular mechanisms of ion permeation of TMEM16B. I mutated two positive charged residues R573 and K540, respectively located at the entrance and inside the putative channel pore and I measured the properties of wild-type and mutant TMEM16B channels expressed in HEK-293 cells using whole-cell and excised inside-out patch clamp experiments...
2017: PloS One
https://www.readbyqxmd.com/read/28027799/regulation-of-epithelial-ion-transport-in-exocrine-glands-by-store-operated-ca-2-entry
#17
REVIEW
Axel R Concepcion, Stefan Feske
Store-operated Ca(2+) entry (SOCE) is a conserved mechanism of Ca(2+) influx that regulates Ca(2+) signaling in many cell types. SOCE is activated by depletion of endoplasmic reticulum (ER) Ca(2+) stores in response to physiological agonist stimulation. After it was first postulated by J.W. Putney Jr. in 1986, SOCE has been described in a large number of non-excitable cell types including secretory cells of different exocrine glands. Here we discuss the mechanisms by which SOCE controls salt and fluid secretion in exocrine glands, with a special focus on eccrine sweat glands...
December 21, 2016: Cell Calcium
https://www.readbyqxmd.com/read/27979828/conditional-genetic-deletion-of-ano1-in-interstitial-cells-of-cajal-impairs-ca-2-transients-and-slow-waves-in-adult-mouse-small-intestine
#18
John Malysz, Simon J Gibbons, Siva A Saravanaperumal, Peng Du, Seth T Eisenman, Chike Cao, Uhtaek Oh, Dieter Saur, Sabine Klein, Tamas Ordog, Gianrico Farrugia
Myenteric plexus interstitial cells of Cajal (ICC-MY) in the small intestine are Kit(+) electrical pacemakers that express the Ano1/TMEM16A Ca(2+)-activated Cl(-) channel, whose functions in the gastrointestinal tract remain incompletely understood. In this study, an inducible Cre-LoxP-based approach was used to advance the understanding of Ano1 in ICC-MY of adult mouse small intestine. Kit(CreERT2/+);Ano1(Fl/Fl) mice were treated with tamoxifen or vehicle, and small intestines (mucosa free) were examined. Quantitative RT-PCR demonstrated ~50% reduction in Ano1 mRNA in intestines of conditional knockouts (cKOs) compared with vehicle-treated controls...
March 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27929144/intermolecular-interactions-in-the-tmem16a-dimer-controlling-channel-activity
#19
Paolo Scudieri, Ilaria Musante, Ambra Gianotti, Oscar Moran, Luis J V Galietta
TMEM16A and TMEM16B are plasma membrane proteins with Ca(2+)-dependent Cl(-) channel function. By replacing the carboxy-terminus of TMEM16A with the equivalent region of TMEM16B, we obtained channels with potentiation of channel activity. Progressive shortening of the chimeric region restricted the "activating domain" to a short sequence close to the last transmembrane domain and led to TMEM16A channels with high activity at very low intracellular Ca(2+) concentrations. To elucidate the molecular mechanism underlying this effect, we carried out experiments based on double chimeras, Forster resonance energy transfer, and intermolecular cross-linking...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27860832/anoctamins-tmem16-proteins-chloride-channels-flirting-with-lipids-and-extracellular-vesicles
#20
Jarred M Whitlock, H Criss Hartzell
Anoctamin (ANO)/TMEM16 proteins exhibit diverse functions in cells throughout the body and are implicated in several human diseases. Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca(2+)-activated Cl(-) channels, most ANO paralogs are Ca(2+)-dependent phospholipid scramblases that serve as channels facilitating the movement (scrambling) of phospholipids between leaflets of the membrane bilayer. Phospholipid scrambling significantly alters the physical properties of the membrane and its landscape and has vast downstream signaling consequences...
February 10, 2017: Annual Review of Physiology
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