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Tmem16a

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https://www.readbyqxmd.com/read/28917060/lipids-and-ions-traverse-the-membrane-by-the-same-physical-pathway-in-the-nhtmem16-scramblase
#1
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-down-regulation-of-bim-expression
#2
Neal R Godse, Nayel I Khan, Zachary A Yochum, Roberto Gomez-Casal, Carolyn Kemp, Daniel J Shiwarski, Raja 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 (HNSCC), raising the possibility of an anti-apoptotic role in malignant cells. The present study investigated this using a multi-modal, translational investigation. EXPERIMENTAL DESIGN: Combination of 1) in vitro HNSCC cell culture experiments assessing cell viability, apoptotic activation, and protein expression 2) in vivo studies assessing similar outcomes, and 3) 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
#3
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
#4
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...
August 29, 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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28603004/ion-channel-signaling-influences-cellular-proliferation-and-phagocyte-activity-during-axolotl-tail-regeneration
#13
Brandon M Franklin, S Randal Voss, Jeffrey L Osborn
Little is known about the potential for ion channels to regulate cellular behaviors during tissue regeneration. Here, we utilized an amphibian tail regeneration assay coupled with a chemical genetic screen to identify ion channel antagonists that altered critical cellular processes during regeneration. Inhibition of multiple ion channels either partially (anoctamin1/Tmem16a, anoctamin2/Tmem16b, KV2.1, KV2.2, L-type CaV channels and H/K ATPases) or completely (GlyR, GABAAR, KV1.5 and SERCA pumps) inhibited tail regeneration...
August 2017: Mechanisms of Development
https://www.readbyqxmd.com/read/28588500/temporal-expression-patterns-of-clock-genes-and-aquaporin-5-anoctamin-1-in-rat-submandibular-gland-cells
#14
Ryouichi Satou, Masaki Sato, Maki Kimura, Yoichi Ishizuka, Masakazu Tazaki, Naoki Sugihara, Yoshiyuki Shibukawa
Circadian rhythms are essential for health and regulate various physiological functions. These rhythms are regulated by a negative-feedback loop involving clock genes in the suprachiasmatic nucleus (SCN) and peripheral tissues. The rate of secretion of salivary substances, ions, and water follows a circadian rhythm, however, the relationship between the molecular mechanism of salivary secretion and peripheral circadian rhythm is not yet clear. Anoctamin 1 (ANO1, also known as TMEM16A) and Aquaporin 5 (AQP5) play an important role in the transport of ions and water in the submandibular glands (SGs)...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28561733/structural-basis-for-anion-conduction-in-the-calcium-activated-chloride-channel-tmem16a
#15
Cristina Paulino, Yvonne Neldner, Andy Km Lam, Valeria Kalienkova, Janine Denise Brunner, Stephan Schenck, Raimund Dutzler
The calcium-activated chloride channel TMEM16A is a member of a conserved protein family that comprises ion channels and lipid scramblases. Although the structure of the scramblase nhTMEM16 has defined the architecture of the family, it was unknown how a channel has adapted to cope with its distinct functional properties. Here we have addressed this question by the structure determination of mouse TMEM16A by cryo-electron microscopy and a complementary functional characterization. The protein shows a similar organization to nhTMEM16, except for changes at the site of catalysis...
May 31, 2017: ELife
https://www.readbyqxmd.com/read/28559311/characterization-of-the-scrambling-domain-of-the-tmem16-family
#16
Sayuri Gyobu, Kenji Ishihara, Jun Suzuki, Katsumori Segawa, Shigekazu Nagata
The TMEM16 protein family has 10 members, each of which carries 10 transmembrane segments. TMEM16A and 16B are Ca(2+)-activated Cl(-) channels. Several other members, including TMEM16F, promote phospholipid scrambling between the inner and outer leaflets of a cell membrane in response to intracellular Ca(2+) However, the mechanism by which TMEM16 proteins translocate phospholipids in plasma membranes remains elusive. Here we show that Ca(2+)-activated, TMEM16F-supported phospholipid scrambling proceeds at 4 °C...
June 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28559167/the-stoichiometry-of-the-tmem16a-ion-channel-determined-in-intact-plasma-membranes-of-cos-7-cells-using-liquid-phase-electron-microscopy
#17
Diana B Peckys, Christof Stoerger, Lorenz Latta, Ulrich Wissenbach, Veit Flockerzi, Niels de Jonge
TMEM16A is a membrane protein forming a calcium-activated chloride channel. A homodimeric stoichiometry of the TMEM16 family of proteins has been reported but an important question is whether the protein resides always in a dimeric configuration in the plasma membrane or whether monomers of the protein are also present in its native state within in the intact plasma membrane. We have determined the stoichiometry of the human (h)TMEM16A within whole COS-7 cells in liquid. For the purpose of detecting TMEM16A subunits, single proteins were tagged by the streptavidin-binding peptide within extracellular loops accessible by streptavidin coated quantum dot (QD) nanoparticles...
May 27, 2017: Journal of Structural Biology
https://www.readbyqxmd.com/read/28546154/synergistic-mucus-secretion-by-histamine-and-il-4-through-tmem16a-in-airway-epithelium
#18
Ju Wan Kang, Yong Hyuk Lee, Min Jeong Kang, Hyun Jae Lee, Ryung Oh, Hyun Jin Min, Wan Namkung, Jae Young Choi, Sang Nam Lee, Chang-Hoon Kim, Joo-Heon Yoon, Hyung-Ju Cho
Histamine is an important mediator of allergic reactions, and mucus hypersecretion is a major allergic symptom. However, the direct effect of histamine on mucus secretion from airway mucosal epithelia has not been clearly demonstrated. TMEM16A is a Ca(2+)-activated chloride channel, and it is closely related to fluid secretion in airway mucosal epithelia. We investigated whether histamine directly induces fluid secretion from epithelial cells or submucosal glands (SMG) and mechanisms related, therewith, in allergic airway diseases...
September 1, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28493701/substituted-2-acylaminocycloalkylthiophene-3-carboxylic-acid-arylamides-as-inhibitors-of-the-calcium-activated-chloride-channel-transmembrane-protein-16a-tmem16a
#19
Eric C Truong, Puay W 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-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa)...
June 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28488084/loop-diuretics-diminish-hemolysis-induced-by-%C3%AE-hemolysin-from-escherichia-coli
#20
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...
June 2017: Journal of Membrane Biology
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