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Tmem16a

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https://www.readbyqxmd.com/read/29331508/compartmentalized-crosstalk-of-cftr-and-tmem16a-ano1-through-epac1-and-adcy1
#1
Joana Lérias, Madalena Pinto, Roberta Benedetto, Rainer Schreiber, Margarida Amaral, Massimo Aureli, Karl Kunzelmann
Airway epithelial cells express both Ca2+ activated TMEM16A/ANO1 and cAMP activated CFTR anion channels. Previous work suggested a significant crosstalk of intracellular Ca2+ and cAMP signaling pathways, leading to activation of both chloride channels. We demonstrate that in airway epithelial cells, stimulation of purinergic or muscarinic G-protein coupled receptors (GPCRs) activates TMEM16A and CFTR. Additional expression of Gq/11 and phospholipase C coupled GPCRs strongly enhanced the crosstalk between Ca2+- and cAMP-dependent signaling...
January 10, 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29277655/phosphatidylinositol-4-5-bisphosphate-cholesterol-and-fatty-acids-modulate-the-calcium-activated-chloride-channel-tmem16a-ano1
#2
José J De Jesús-Pérez, Silvia Cruz-Rangel, Ángeles E Espino-Saldaña, Ataúlfo Martínez-Torres, Zhiqiang Qu, H Criss Hartzell, Nancy E Corral-Fernandez, Patricia Pérez-Cornejo, Jorge Arreola
The TMEM16A-mediated Ca2+-activated Cl- current drives several important physiological functions. Membrane lipids regulate ion channels and transporters but their influence on members of the TMEM16 family is poorly understood. Here we have studied the regulation of TMEM16A by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), cholesterol, and fatty acids using patch clamp, biochemistry and fluorescence microscopy. We found that depletion of membrane PI(4,5)P2 causes a decline in TMEM16A current that is independent of cytoskeleton, but is partially prevented by removing intracellular Ca2+...
December 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29236691/activation-mechanism-of-the-calcium-activated-chloride-channel-tmem16a-revealed-by-cryo-em
#3
Cristina Paulino, Valeria Kalienkova, Andy K M Lam, Yvonne Neldner, Raimund Dutzler
The calcium-activated chloride channel TMEM16A is a ligand-gated anion channel that opens in response to an increase in intracellular Ca2+ concentration. The protein is broadly expressed and contributes to diverse physiological processes, including transepithelial chloride transport and the control of electrical signalling in smooth muscles and certain neurons. As a member of the TMEM16 (or anoctamin) family of membrane proteins, TMEM16A is closely related to paralogues that function as scramblases, which facilitate the bidirectional movement of lipids across membranes...
December 13, 2017: Nature
https://www.readbyqxmd.com/read/29236684/cryo-em-structures-of-the-tmem16a-calcium-activated-chloride-channel
#4
Shangyu Dang, Shengjie Feng, Jason Tien, Christian J Peters, David Bulkley, Marco Lolicato, Jianhua Zhao, Kathrin Zuberbühler, Wenlei Ye, Lijun Qi, Tingxu Chen, Charles S Craik, Yuh Nung Jan, Daniel L Minor, Yifan Cheng, Lily Yeh Jan
Calcium-activated chloride channels (CaCCs) encoded by TMEM16A control neuronal signalling, smooth muscle contraction, airway and exocrine gland secretion, and rhythmic movements of the gastrointestinal system. To understand how CaCCs mediate and control anion permeation to fulfil these physiological functions, knowledge of the mammalian TMEM16A structure and identification of its pore-lining residues are essential. TMEM16A forms a dimer with two pores. Previous CaCC structural analyses have relied on homology modelling of a homologue (nhTMEM16) from the fungus Nectria haematococca that functions primarily as a lipid scramblase, as well as subnanometre-resolution electron cryo-microscopy...
December 13, 2017: Nature
https://www.readbyqxmd.com/read/29229864/cytoplasmic-cl-couples-membrane-remodeling-to-epithelial-morphogenesis
#5
Mu He, Wenlei Ye, Won-Jing Wang, Eirish S Sison, Yuh Nung Jan, Lily Yeh Jan
Chloride is the major free anion in the extracellular space (>100 mM) and within the cytoplasm in eukaryotes (10 ∼ 20 mM). Cytoplasmic Cl- level is dynamically regulated by Cl- channels and transporters. It is well established that movement of Cl- across the cell membrane is coupled with cell excitability through changes in membrane potential and with water secretion. However, whether cytoplasmic Cl- plays additional roles in animal development and tissue homeostasis is unknown. Here we use genetics, cell biological and pharmacological tools to demonstrate that TMEM16A, an evolutionarily conserved calcium-activated chloride channel (CaCC), regulates cytoplasmic Cl- homeostasis and promotes plasma membrane remodeling required for mammalian epithelial morphogenesis...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29187602/tmem16a-and-tmem16b-channel-proteins-generate-ca2-activated-cl-currentand-regulate-melatonin-secretion-in-rat-pineal-glands
#6
Hisao Yamamura, Kaori Nishimura, Yumiko Hagihara, Yoshiaki Suzuki, Yuji Imaizumi
Pinealocytes regulate circadian rhythm by synthesizing and secreting melatonin. These cells generate action potentials, however, the contribution of specific ion channels to melatonin secretion from pinealocytes remains unclear. In this study, the involvement and molecular identity of Ca2+-activated Cl- (ClCa) channels in the regulation of melatonin secretion were examined in rat pineal glands. Treatment with the ClCa channel blockers, niflumic acid or T16Ainh-A01, significantly reduced melatonin secretion in pineal glands...
November 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29160910/epithelial-disruptions-but-not-immune-cell-invasion-induced-secretory-dysfunction-following-innate-immune-activation-in-a-novel-model-of-acute-salivary-gland-injury
#7
Abeer Shaalan, Guy Carpenter, Gordon Proctor
BACKGROUND: Salivary gland (SG) injurious agents are all translated into loss of salivation (xerostomia). An association has been established between activation of innate immunity and salivary gland injury and dysfunction. However, it remains unclear how the secretory epithelia respond by halting saliva production. METHODS: C57BL/6 submandibular glands (SMGs) were acutely challenged using a single dose of the innate immune stimulant: polyinosinic-polycytidylic acid (poly (I:C))...
November 21, 2017: Journal of Oral Pathology & Medicine
https://www.readbyqxmd.com/read/29159026/highlights-for-the-6th-international-ion-channel-conference-ion-channel-structure-function-disease-and-therapeutics
#8
Limei Wang, Kewei Wang
To foster communication and interactions amongst international scholars and scientists in the field of ion channel research, the 6th International Ion Channel Conference (IICC-2017) was held between June 23-27, 2017 in the eastern coastal city of Qingdao, China. The meeting consisted of 450 attendees and 130 speakers and poster presenters. The program consisted of research progress, new findings and ongoing studies that were focused on (1) Ion channel structure and function; (2) Ion channel physiology and human diseases; (3) Ion channels as targets for drug discovery; (4) Technological advances in ion channel research...
November 2017: Acta Pharmaceutica Sinica. B
https://www.readbyqxmd.com/read/29156699/cell-specific-regulation-of-proliferation-by-ano1-tmem16a-in-breast-cancer-with-different-er-pr-and-her2-status
#9
Huizhe Wu, Hui Wang, Shu Guan, Jing Zhang, Qiuchen Chen, Xiaodong Wang, Ke Ma, Pengfei Zhao, Haishan Zhao, Weifan Yao, Feng Jin, Qinghuan Xiao, Minjie Wei
The calcium-activated chloride channel Ano1 (TMEM16A) is overexpressed in many tumors. However, conflicting data exist regarding the role of Ano1 in cell proliferation. Here, we performed immunohistochemistry to investigate the expression of Ano1 and Ki67 in 403 patients with breast cancer, and analyzed the association between the expression of Ano1 and Ki67 in breast cancer subtypes categorized according to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29134661/regulation-of-tmem16a-ano1-and-tmem16f-ano6-ion-currents-and-phospholipid-scrambling-by-ca-2-and-plasma-membrane-lipid
#10
Rainer Schreiber, Jiraporn Ousingsawat, Podchanart Wanitchakool, Lalida Sirianant, Roberta Benedetto, Karina Reiss, Karl Kunzelmann
TMEM16/anoctamin proteins form Ca(2+) activated ion channels or phospholipid scramblases. We found that both TMEM16A/ANO1 and TMEM16F/ANO6 produced Cl(-) currents when activated by intracellular Ca(2+) , but only TMEM16F was able to expose phosphatidylserine to the outer leaflet of the plasma membrane. Mutations within TMEM16F or TMEM16A/F chimeras similarly changed Cl(-) currents and phospholipid scrambling, suggesting the same intramolecular pathway for Cl(-) and phospholipids. When overexpressed, TMEM16A and TMEM16F produced spontaneous Cl(-) currents at 37°C even at resting intracellular Ca(2+) levels, which was abolished by inhibition of phospholipase A2 (PLA2 )...
November 14, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29129885/-airway-epithelial-cell-differentiation-and-hypersecretion-the-role-of-il-13-clca1-and-tmem16a
#11
Mitsuko Kondo
No abstract text is available yet for this article.
2017: Arerugī, [Allergy]
https://www.readbyqxmd.com/read/29123240/dna-methylation-regulates-tmem16a-ano1-expression-through-multiple-cpg-islands-in-head-and-neck-squamous-cell-carcinoma
#12
Andrey Finegersh, Scott Kulich, Theresa Guo, Alexander V Favorov, Elana J Fertig, Ludmila V Danilova, Daria A Gaykalova, Joseph A Califano, Umamaheswar Duvvuri
ANO1 is a calcium-activated chloride channel that is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and other cancers. While ANO1 expression negatively correlates with survival in several cancers, its epigenetic regulation is poorly understood. We analyzed HNSCC samples from TCGA and a separate dataset of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples to identify differentially methylated regions. E6 and E7 transfected normal oral keratinocytes (NOK) were used to induce hypermethylation of the ANO1 promoter...
November 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29098165/a-trpm4-inhibitor-9-phenanthrol-inhibits-glucose-and-glucagon-like-peptide-1-induced-insulin-secretion-from-rat-islets-of-langerhans
#13
Zuheng Ma, Anneli Björklund, Md Shahidul Islam
Pancreatic β-cells express several ion channels of the transient receptor potential family, which play important roles in mediating the stimulus-secretion coupling. One of these channels, the TRPM4 is a Ca(2+)-activated monovalent cation channel. This channel is inhibited by 9-phenanthrol, which also inhibits the TMEM16a Cl(-) channel, and activates the Ca(2+)-activated K(+) channel, Kca3.1. The net effects of ion-channel modulation by 9-phenantherol on the insulin secretion remain unclear. We tested the effects of 9-phenanthrol on glucose- and GLP-1-induced insulin secretion from isolated rat islets in static incubations...
2017: Journal of Diabetes Research
https://www.readbyqxmd.com/read/29081444/ca-2-calmodulin-dependent-protein-kinase-ii-%C3%AE-dependent-serine727-phosphorylation-is-required-for-tmem16a-ca-2-activated-cl-channel-regulation-in-cerebrovascular-cells
#14
Cai-Xia Lin, Xiao-Fei Lv, Feng Yuan, Xiang-Yu Li, Ming-Ming Ma, Can-Zhao Liu, Jia-Guo Zhou, Guan-Lei Wang, Yong-Yuan Guan
BACKGROUND: TMEM16A is a critical component of Ca(2+)-activated chloride channels (CaCCs) and mediates basilar arterial smooth muscle cell (BASMC) proliferation in hypertensive cerebrovascular remodeling. CaMKII is a negative regulator of CaCC, and four CaMKII isoforms (α, β, γ and δ) are expressed in vasculature; however, it is unknown which and how CaMKII isoforms affect TMEM16A-associated CaCC and BASMC proliferation.Methods and Results:Patch clamp and small interfering RNA (siRNA) knockdown of different CaMKII isoforms revealed that only CaMKIIγ inhibited native Ca(2+)-activated chloride currents (ICl...
October 28, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/29065356/bypassing-cftr-dysfunction-in-cystic-fibrosis-with-alternative-pathways-for-anion-transport
#15
REVIEW
Hongyu Li, Johanna J Salomon, David N Sheppard, Marcus A Mall, Luis Jv Galietta
One therapeutic strategy for cystic fibrosis (CF) seeks to restore anion transport to affected epithelia by targeting other apical membrane Cl(-) channels to bypass dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. The properties and regulation of the Ca(2+)-activated Cl(-) channel TMEM16A argue that long-acting small molecules which target directly TMEM16A are required to overcome CFTR loss. Through genetic studies of lung diseases, SLC26A9, a member of the solute carrier 26 family of anion transporters, has emerged as a promising target to bypass CFTR dysfunction...
October 21, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28963502/epithelial-chloride-transport-by-cftr-requires-tmem16a
#16
Roberta Benedetto, Jiraporn Ousingsawat, Podchanart Wanitchakool, Yong Zhang, Michael J Holtzman, Margarida Amaral, Jason R Rock, Rainer Schreiber, Karl Kunzelmann
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is the secretory chloride/bicarbonate channel in airways and intestine that is activated through ATP binding and phosphorylation by protein kinase A, but fails to operate in cystic fibrosis (CF). TMEM16A (also known as anoctamin 1, ANO1) is thought to function as the Ca(2+) activated secretory chloride channel independent of CFTR. Here we report that tissue specific knockout of the TMEM16A gene in mouse intestine and airways not only eliminates Ca(2+)-activated Cl(-) currents, but unexpectedly also abrogates CFTR-mediated Cl(-) secretion and completely abolishes cAMP-activated whole cell currents...
September 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28955034/microrna-9-downregulates-the-ano1-chloride-channel-and-contributes-to-cystic-fibrosis-lung-pathology
#17
Florence Sonneville, Manon Ruffin, Christelle Coraux, Nathalie Rousselet, Philippe Le Rouzic, Sabine Blouquit-Laye, Harriet Corvol, Olivier Tabary
Cystic fibrosis results from reduced cystic fibrosis transmembrane conductance regulator protein activity leading to defective epithelial ion transport. Ca2+-activated Cl- channels mediate physiological functions independently of cystic fibrosis transmembrane conductance regulator. Anoctamin 1 (ANO1/TMEM16A) was identified as the major Ca2+-activated Cl- channel in airway epithelial cells, and we recently demonstrated that downregulation of the anoctamin 1 channel in cystic fibrosis patients contributes to disease severity via an unknown mechanism...
September 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28917060/lipids-and-ions-traverse-the-membrane-by-the-same-physical-pathway-in-the-nhtmem16-scramblase
#18
Tao Jiang, Kuai Yu, H Criss Hartzell, Emad Tajkhorshid
From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane...
September 16, 2017: ELife
https://www.readbyqxmd.com/read/28899969/tmem16a-ano1-inhibits-apoptosis-via-downregulation-of-bim-expression
#19
Neal R Godse, Nayel Khan, Zachary A Yochum, Roberto Gomez-Casal, Carolyn Kemp, Daniel J Shiwarski, Raja S Seethala, Scott Kulich, Mukund Seshadri, Timothy F Burns, Umamaheswar Duvvuri
Purpose: TMEM16A is a calcium-activated chloride channel that is amplified in a variety of cancers, including 30% of head and neck squamous cell carcinomas (HNSCCs), raising the possibility of an anti-apoptotic role in malignant cells. This study investigated this using a multimodal, translational investigation.Experimental Design: Combination of (i) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression (ii) in vivo studies assessing similar outcomes, and (iii) molecular and staining analysis of human HNSCC samples...
September 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28893247/cell-specific-mechanisms-of-tmem16a-ca2-activated-chloride-channel-in-cancer
#20
REVIEW
Hui Wang, Liang Zou, Ke Ma, Jiankun Yu, Huizhe Wu, Minjie Wei, Qinghuan Xiao
TMEM16A (known as anoctamin 1) Ca2+-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma...
September 11, 2017: Molecular Cancer
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