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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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. Ca(2+)-activated Cl(-) channels mediate physiological functions independently of cystic fibrosis transmembrane conductance regulator. Anoctamin 1 (ANO1/TMEM16A) was identified as the major Ca(2+)-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
#9
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
#10
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-ca-2-activated-chloride-channel-in-cancer
#11
REVIEW
Hui Wang, Liang Zou, Ke Ma, Jiankun Yu, Huizhe Wu, Minjie Wei, Qinghuan Xiao
TMEM16A (known as anoctamin 1) Ca(2+)-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
https://www.readbyqxmd.com/read/28852814/identification-of-resveratrol-an-herbal-compound-as-an-activator-of-the-calcium-activated-chloride-channel-tmem16a
#12
Ran Chai, Yafei Chen, Hongbo Yuan, Xuzhao Wang, Shuai Guo, Jinlong Qi, Hailin Zhang, Yong Zhan, Hailong An
Calcium-activated chloride channels (CaCCs) play vital roles in a variety of physiological processes. Dysfunction of the CaCCs is implicated in many diseases. Drug discovery targeting at CaCCs has recently become possible with the determination that TMEM16A is the molecular identity of CaCCs. In this study, we demonstrated that resveratrol (RES), a Chinese traditional medicine compound, is a novel activator of TMEM16A. The yellow fluorescence protein quenching assay and measurement of intracellular calcium fluorescence intensity show that RES activates TMEM16A channels in an intracellular Ca(2+)-independent way...
October 2017: Journal of Membrane Biology
https://www.readbyqxmd.com/read/28800723/a-clca-regulatory-protein-present-in-the-chemosensory-cilia-of-olfactory-sensory-neurons-induces-a-ca-2-activated-cl-current-when-transfected-into-hek293
#13
Casilda V Mura, Ricardo Delgado, María Graciela Delgado, Diego Restrepo, Juan Bacigalupo
BACKGROUND: CLCA is a family of metalloproteases that regulate Ca(2+)-activated Cl(-) fluxes in epithelial tissues. In HEK293 cells, CLCA1 promotes membrane expression of an endogenous Anoctamin 1 (ANO1, also termed TMEM16A)-dependent Ca(2+)-activated Cl(-) current. Motif architecture similarity with CLCA2, 3 and 4 suggested that they have similar functions. We previously detected the isoform CLCA4L in rat olfactory sensory neurons, where Anoctamin 2 is the principal chemotransduction Ca(2+)-activated Cl(-) channel...
August 11, 2017: BMC Neuroscience
https://www.readbyqxmd.com/read/28796813/a-novel-organotypic-3d-sweat-gland-model-with-physiological-functionality
#14
Patricia Klaka, Sabine Grüdl, Bernhard Banowski, Melanie Giesen, Andrea Sättler, Peter Proksch, Thomas Welss, Thomas Förster
Dysregulated human eccrine sweat glands can negatively impact the quality-of-life of people suffering from disorders like hyperhidrosis. Inability of sweating can even result in serious health effects in humans affected by anhidrosis. The underlying mechanisms must be elucidated and a reliable in vitro test system for drug screening must be developed. Here we describe a novel organotypic three-dimensional (3D) sweat gland model made of primary human eccrine sweat gland cells. Initial experiments revealed that eccrine sweat gland cells in a two-dimensional (2D) culture lose typical physiological markers...
2017: PloS One
https://www.readbyqxmd.com/read/28754608/inflammatory-mediators-mediate-airway-smooth-muscle-contraction-through-a-gpcr-tmem16a-vdcc-axis-and-contribute-to-bronchial-hyperresponsiveness-in-asthma
#15
Pei Wang, Wei Zhao, Jie Sun, Tao Tao, Xin Chen, Yan-Yan Zheng, Cheng-Hai Zhang, Zhong Chen, Yun-Qian Gao, Fan She, Ye-Qiong Li, Li-Sha Wei, Ping Lu, Cai-Ping Chen, Ji Zhou, Da-Quan Wang, Liang Chen, Xiao-Hao Shi, Linhong Deng, Ronghua ZhuGe, Hua-Qun Chen, Min-Sheng Zhu
BACKGROUND: Allergic inflammation has long been implicated in asthmatic hyperresponsiveness of airway smooth muscle (ASM), but its mechanism underlying remains incompletely understood. Serving as GPCR agonists, several inflammatory mediators can induce membrane depolarization, contract ASM and augment cholinergic contractile response. We hypothesized that the signal cascade integrating on membrane depolarization by the mediators might involve asthmatic hyperresponsiveness. OBJECTIVE: We sought to investigate the signalling transduction of inflammatory mediators in ASM contraction and assess its contribution in the genesis of hyperresponsiveness...
July 25, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28733893/effects-of-new-generation-tmem16a-inhibitors-on-calcium-activated-chloride-currents-in-rabbit-urethral-interstitial-cells-of-cajal
#16
Stephen Fedigan, Eamonn Bradley, Timothy Webb, Roddy J Large, Mark A Hollywood, Keith D Thornbury, Noel G McHale, Gerard P Sergeant
Interstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit Ca(2+)-activated Cl(-) currents (I ClCa) that are important for the development of urethral tone. Here, we examined if TMEM16A (ANO1) contributed to this activity by examining the effect of "new-generation" TMEM16A inhibitors, CACCinh-A01 and T16Ainh-A01, on I ClCa recorded from freshly isolated rabbit urethral ICC (RUICC) and on contractions of intact strips of rabbit urethra smooth muscle. Real-time quantitative PCR experiments demonstrated that TMEM16A was highly expressed in rabbit urethra smooth muscle, in comparison to TMEM16B and TMEM16F...
July 21, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/28668303/ca-2-activated-cl-current-is-antiarrhythmic-by-reducing-both-spatial-and-temporal-heterogeneity-of-cardiac-repolarization
#17
Bence Hegyi, Balázs Horváth, Krisztina Váczi, Mónika Gönczi, Kornél Kistamás, Ferenc Ruzsnavszky, Roland Veress, Leighton T Izu, Ye Chen-Izu, Tamás Bányász, János Magyar, László Csernoch, Péter P Nánási, Norbert Szentandrássy
The role of Ca(2+)-activated Cl(-) current (ICl(Ca)) in cardiac arrhythmias is still controversial. It can generate delayed afterdepolarizations in Ca(2+)-overloaded cells while in other studies incidence of early afterdepolarization (EAD) was reduced by ICl(Ca). Therefore our goal was to examine the role of ICl(Ca) in spatial and temporal heterogeneity of cardiac repolarization and EAD formation. Experiments were performed on isolated canine cardiomyocytes originating from various regions of the left ventricle; subepicardial, midmyocardial and subendocardial cells, as well as apical and basal cells of the midmyocardium...
August 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28666267/cell-specific-regulation-of-proliferation-by-ano1-tmem16a-in-breast-cancer-with-different-er-pr-and-her2-status
#18
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)...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28648509/pendred-syndrome
#19
REVIEW
Jean-Louis Wémeau, Peter Kopp
Pendred syndrome is an autosomal recessive disorder that is classically defined by the combination of sensorineural deafness/hearing impairment, goiter, and an abnormal organification of iodide with or without hypothyroidism. The hallmark of the syndrome is the impaired hearing, which is associated with inner ear malformations such as an enlarged vestibular aqueduct (EVA). The thyroid phenotype is variable and may be modified by the nutritional iodine intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4/PDS gene, which encodes the multifunctional anion exchanger pendrin...
March 2017: Best Practice & Research. Clinical Endocrinology & Metabolism
https://www.readbyqxmd.com/read/28616863/contrasting-effects-of-phosphatidylinositol-4-5-bisphosphate-on-cloned-tmem16a-and-tmem16b-channels
#20
Chau M Ta, Kathryn E Acheson, Nils J G Rorsman, Remco C Jongkind, Paolo Tammaro
BACKGROUND AND PURPOSE: Ca(2+) -activated Cl(-) channels (CaCCs) are gated open by a rise in intracellular Ca(2+) concentration ([Ca(2+) ]i ), typically provoked by activation of Gq -protein coupled receptors (Gq PCR). Gq PCR activation initiates depletion of plasmalemmal phosphatidylinositol 4,5-bisphosphate (PIP2 ). Here, we determined whether PIP2 acts as a signalling lipid for CaCCs coded by the TMEM16A and TMEM16B genes. EXPERIMENTAL APPROACH: Patch-clamp electrophysiology, in conjunction with genetically encoded systems to control cellular PIP2 content, was used to define the mechanism of action of PIP2 on TMEM16A and TMEM16B channels...
September 2017: British Journal of Pharmacology
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