ライフサイエンスコーパス: TMEM16A

1 nnel (CaCC) anoctamin 1 (ANO1, also known as TMEM16A).

2 is necessary for apoCaM preassociation with TMEM16A.

3 are hypoxic, and oxidative stress activates TMEM16A.

4 expressed, purified, and reconstituted human TMEM16A.

5 ng CFTR, ClC-2, ClC-3, CLCA, Bestrophin, and TMEM16A.

6 loride secretion mediated by the ion channel TMEM16A.

7 ferrostatin-1 largely reduced activation of TMEM16A.

8 involve changes in pH and chloride flux via TMEM16A.

9 ibitor of calcium-activated chloride channel TMEM16A.

10 Understanding how TMEM16A/16B are regulated by Ca(2+) is critical for defi

11 esults reveal multidimensional regulation of TMEM16A/16B by preassociated apoCaM and introduce ChIMP

12 ee calmodulin (apoCaM) is preassociated with TMEM16A/16B channel complexes.

13 ation of TMEM16A in HPV-positive HNSCC makes TMEM16A a poor therapeutic target in HPV-positive HNSCC,

14 Ano1 (Tmem16a), a Ca(2+)-activated Cl(-) channel, is an ion ch

15 Best2, 3, or 4, or transmembrane member 16A (TMEM16A), a member of another channel family.

16 We determined that Tmem16a, a member of an evolutionarily conserved family

17 tabilizing mutation (I551P) that facilitates TMEM16A activation, revealing atomistic details of the i

18 but reduced the EC(50) for Ca(2+)-dependent TMEM16A activation.

19 The TMEM16A activators increased CaCC conductance in human s

20 Increase in TMEM16A activity occurred within minutes of exposure to

21 show that a low proton concentration reduces TMEM16A activity while maximum activation is obtained wh

22 CA1 as the first secreted direct modifier of TMEM16A activity, delineating a unique mechanism to incr

23 if impaired the ability of VWA to potentiate TMEM16A activity, suggesting that CLCA1-TMEM16A interact

24 50% CFTR activity and approximately 50% non-Tmem16a activity.

25 acidification and provide evidence that ANO1/TMEM16A acts to attenuate this pH shift.

26 TMEM16A also has a profound impact on phosphoproteome re

27 TMEM16A also was required for peripheral blood vessel co

28 TMEM16A (also known as anoctamin 1, ANO1) is thought to

29 Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-a

30 ABSTRACT: Transmembrane protein 16A (TMEM16A), also known as ANO1, the pore-forming subunit o

31 on of recently discovered transmembrane 16A (TMEM16A), also termed Anoctamin 1, chloride (Cl(-)) chan

32 on of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cell

33 TMEM16A alternative splicing provides a mechanism for tu

34 nd pharmacological tools to demonstrate that TMEM16A, an evolutionarily conserved calcium-activated c

35 lic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10b

36 Our results demonstrate that both Tmem16A and Best2 generate Ca(2+)-activated Cl(-) curren

37 Heterologous expression of Tmem16A and Best2 transcripts in HEK293 cells produced C

38 the Ca(2+)-gated Cl(-) currents generated by Tmem16A and Best2, members from two distinct families of

39 enous CLCA1 increases cell surface levels of TMEM16A and cellular binding experiments indicate CLCA1

40 However, both large and small BECs express TMEM16A and exhibit Ca(2+)-activated Cl(-) efflux in res

41 h clamp experiments to analyze activation of TMEM16A and growth of renal cysts.

42 includes the Ca(2+)-activated Cl(-) channels TMEM16A and TMEM16B and a small-conductance, Ca(2+)-acti

43 Mammalian TMEM16A and TMEM16B are Ca(2+)-activated Cl(-) channels

44 TMEM16A and TMEM16B are calcium-activated chloride chann

45 TMEM16A and TMEM16B are molecular components of the phys

46 Having recently identified TMEM16A and TMEM16B as CaCCs, we further show that TMEM1

47 nexpected role for the putative pore-loop of TMEM16A and TMEM16B channels in the control of the whole

48 We show that TMEM16A and TMEM16B display fast and slow gating.

49 er chimeras within the putative pore-loop of TMEM16A and TMEM16B led to the identification of a regio

50 currents carried via transmembrane proteins TMEM16A and TMEM16B regulate diverse processes including

51 Calcium-activated chloride channels TMEM16A and TMEM16B support important physiological proc

52 Moreover, mouse TMEM16A and TMEM16B yield CaCCs in Axolotl oocytes and m

53 without altering the nanoscale properties of TMEM16A and TRPV4 surface clusters or their colocalizati

54 Interestingly, the tracheas of both the Tmem16a(-/-) and the CFTR(-/-) mice exhibited similar co

55 Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca(2+)-activated Cl(-) c

56 nductance regulator (CFTR), anoctamin-1(ANO1/TMEM16A) and the glycine receptor (GlyR), revealed that

57 c markers-namely, alpha-amylase, cystatin C, TMEM16A, and NKCC1.

58 Activation of TMEM16A- and CFTR-dependent chloride secretion strongly

59 Recently, TMEM16A (ANO1) and -B were shown to be critical componen

60 ly members to be functionally characterized, TMEM16A (ANO1) and TMEM16B (ANO2), form Ca(2+)-activated

61 TMEM16A (ANO1) functions as a calcium-activated chloride

62 TMEM16A (ANO1) is a calcium-activated chloride channel (

63 channel proteins transmembrane protein 16A (TMEM16A, ANO1), leucine-rich repeat (LRR)-containing 8 (

64 ansmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1), drives cyst enlargement in polycy

65 1 (CLCA1) modulates the activity of the CaCC TMEM16A/Anoctamin 1 (ANO1) by directly engaging the chan

66 cells in a paracrine fashion, and endogenous TMEM16A/Anoctamin1 conducts the currents.

67 cell-attached patches that were inhibited by TMEM16A antibodies and were of similar amplitude to reco

68 to those expressed in native cells, yet only Tmem16A appears to be a critical component of the acinar

69 d chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestin

70 Recent studies have unequivocally identified TMEM16A as a glandular epithelial CaCC.

71 Our data identify Tmem16a as a novel regulator of epithelial and smooth mu

72 The identification of ANO1/TMEM16A as the likely calcium-dependent chloride channel

73 as an expression system, we have identified TMEM16A as the Xenopus oocyte CaCC.

74 have developed antibodies specific for mouse TMEM16A, as evidenced by the absence of immunoreactivity

75 tes two distinct Ca(2+)-dependent effects on TMEM16A, as revealed by expression of dominant-negative

76 the chondrogenic mesenchyme does not express Tmem16a at any time, we propose that the cartilage ring

77 cid 623, which enables voltage activation of TMEM16A at non-saturating [Ca(2+) ]i .

78 nt with the hypothesis that CLCA1 stabilizes TMEM16A at the cell surface by preventing its internaliz

79 TR or the calcium-activated chloride channel TMEM16A attenuated the proinflammatory cytokines interle

80 but not P2Y receptor-mediated activation of TMEM16A attenuates IL-8 secretion in respiratory epithel

81 e pore-loop of TMEM16A with that of TMEM16B (TMEM16A-B channels) reduced the currents by approximatel

82 TMEM16F of the TMEM16 family that includes TMEM16A/B Ca(2+)-activated Cl(-) channels (CaCCs) is lin

83 In contrast to its paralogs, the TMEM16A/B calcium-activated chloride channels, mouse TME

84 TMEM16A belongs to a family of integral membrane protein

85 eported calcium-activated chloride channels (TMEM16A, Bestrophin-1, ClC2, and SLC26A9), both features

86 tance, providing further evidence for direct TMEM16A binding.

87 Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis

88 e intestinal calcium-activated Cl(-) channel TMEM16A by a voltage-independent inhibition mechanism wi

89 tion by the structure determination of mouse TMEM16A by cryo-electron microscopy and a complementary

90 These findings indicate that activation of TMEM16A by lipid peroxidation drives growth of renal cys

91 tic potential of the selective activation of TMEM16A by the CLCA1 VWA domain in loss-of-function chlo

92 Noise analysis showed that protons regulate TMEM16A by tuning its open probability without modifying

93 head group that mediate its interaction with TMEM16A by using patch- and two-electrode voltage-clamp

94 on of two residues in the pore region of the TMEM16A Ca(2+)-activated Cl(-) channel convert it into a

95 voltage-dependent Ca(2+) channels (VDCCs) or TMEM16A Ca(2+)-activated Cl(-) channels significantly ch

96 efflux and osmotic cell shrinkage by opening TMEM16A Ca(2+)-activated Cl(-) channels.

97 compounds revealed compounds that activated TMEM16A CaCC conductance without increasing cytoplasmic

98 Our data suggest that TMEM16A CaCC-mediated Cl(-) secretion appears to be nece

99 TMEM16A-CaCC blockers, including those identified here,

100 ing intense interest in the mechanism behind TMEM16A-CaCC calcium-dependent gating, comprehensive sur

101 in the dimerization domain affect functional TMEM16A-CaCC channel expression, as expected from its cr

102 creen to identify small-molecule blockers of TMEM16A-CaCC channels.

103 versus anion selectivity of TMEM16F-SCAN and TMEM16A-CaCC channels.

104 We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in pr

105 Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM c

106 ed here permit pharmacological dissection of TMEM16A/CaCC function and are potential development cand

107 We conclude that TMEM16A carries nearly all CaCC current in salivary glan

108 ositol (4,5)-bisphosphate (PIP(2)) regulates TMEM16A channel activation and desensitization via bindi

109 llular processes and second messengers alter TMEM16A channel gating.

110 ts in arterial myocytes that were blocked by TMEM16A channel inhibitory antibodies, RNAi-mediated sel

111 hibitory antibodies, RNAi-mediated selective TMEM16A channel knockdown, removal of extracellular calc

112 small molecule with a biphasic effect on the TMEM16A channel, anthracene-9-carboxylic acid (A9C), we

113 voked Cl(-) currents conducted by endogenous TMEM16A channels expressed in Xenopus laevis oocytes, us

114 Furthermore, deficiency of TMEM16A channels in endothelial cells resulted in increa

115 d by nonselective cation channels stimulates TMEM16A channels to induce myogenic constriction.

116 Furthermore, whole-cell currents mediated by TMEM16A channels were approximately six times larger tha

117 Membrane stretch activates arterial myocyte TMEM16A channels, leading to membrane depolarization and

118 and were of similar amplitude to recombinant TMEM16A channels.

119 g Xenopus laevis, which endogenously express TMEM16A channels.

120 losing M-type potassium channels and opening TMEM16A chloride channels, resulting in the production o

121 lecule TMEM16A inhibitors that fully blocked TMEM16A chloride current with an IC(50) < 10 muM, withou

122 ivators were identified that fully inhibited TMEM16A Cl(-) conductance, providing further evidence fo

123 enetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in

124 tinuous application of Ca(2+), we found that TMEM16A-conducted currents decay shortly after patch exc

125 to excised inside-out patches, we found that TMEM16A-conducted currents decayed shortly after patch e

126 ble dephosphorylation of PI(4,5)P(2) reduces TMEM16A-conducted currents.

127 intraluminal pH and test the idea that ANO1/TMEM16A contributes to luminal pH balance.

128 tivated chloride channels (CaCCs) encoded by TMEM16A control neuronal signalling, smooth muscle contr

129 Understanding how TMEM16A controls these physiological processes and how i

130 physical interactions between calmodulin and TMEM16A could not be detected in copurification experime

131 acellular surface of excised patches sped up TMEM16A current rundown to nearly twice as fast.

132 ulating agents altered the speed kinetics of TMEM16A current rundown.

133 Acetylcholine stimulated TMEM16A currents by activating Ca(2+) influx through sur

134 2+) stores, did not alter swelling-activated TMEM16A currents.

135 high degree of similarity with heterologous TMEM16A currents.

136 ate at the 4' position effectively recovered TMEM16A currents.

137 TMEM16A deletion in IAS-SMCs abolishes the effects of mo

138 oreover, molecular actors identified in this TMEM16A-dependent EGFR-induced calcium signaling pathway

139 hat all mice homozygous for a null allele of Tmem16a died within one month of birth and exhibited sev

140 r proton concentrations ([H(+) ]o ) on mouse TMEM16A expressed in HEK-293 cells using whole-cell and

141 ases of pancreatic cancer and high levels of TMEM16A expression are correlated with low patient survi

142 We demonstrate that the lower levels of TMEM16A expression in HPV-positive tumors can be attribu

143 which is attributable to an upregulation of TMEM16A expression in PASMCs.

144 Genetic analysis implicated altered TMEM16A expression in poor patient recovery from ischemi

145 We also show that TMEM16A expression is decreased in HPV-positive HNSCC at

146 The TMEM16A expression pattern established in this study thu

147 Members of the Anoctamin (Ano)/TMEM16A family have recently been identified as essentia

148 cript in addition to other paralogues of the Tmem16a family.

149 PV-negative cell lines are more dependent on TMEM16A for survival than HPV-positive cell lines.

150 TMEM16A forms a dimer with two pores.

151 TMEM16A forms calcium-activated chloride channels (CaCCs

152 Depletion of Tmem16a from the tadpole skin results in dysregulated mu

153 be useful as pharmacological tools to study TMEM16A function and as potential drug development candi

154 rders, and for pharmacological dissection of TMEM16A function.

155 Here we assessed the regulation of TMEM16A gating by recording Ca(2+)-evoked Cl(-) currents

156 to investigate a possible role of PIP(2) in TMEM16A gating.

157 Downregulation of TMEM16A gene expression in primary cultures of rat PASMC

158 report that tissue specific knockout of the TMEM16A gene in mouse intestine and airways not only eli

159 mily members linked to tracheomalacia (mouse TMEM16A), gnathodiaphyseal dysplasia (human TMEM16E), ab

160 Mice lacking vascular TMEM16A had lower systemic blood pressure and a decrease

161 w gating, but, mutating 448 AVK451 to RSQ in TMEM16A has little effect.

162 d Cl(-) channel (CaCC), Anoctamin 1 (Ano1 or TMEM16A), has been implicated in vital physiological fun

163 TMEM16A, however, appeared to contribute little to unsti

164 For example, TMEM16A ICl activates slowly with a non-mono-exponential

165 Protons regulate TMEM16A in a voltage-independent manner, regardless of c

166 data demonstrate fundamentally new roles of TMEM16A in differentiated epithelial cells: TMEM16A prov

167 pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of T

168 calcium-activated chloride channels such as TMEM16a in GPCR-activation of itch nerve terminals.

169 fore, we suspect that the down-regulation of TMEM16A in HPV-positive HNSCC makes TMEM16A a poor thera

170 ctures of the transmembrane domains of mouse TMEM16A in nanodiscs and in lauryl maltose neopentyl gly

171 Here, we show a functional role for TMEM16A in tumor growth.

172 ishes the Ca(2+) dependence of reconstituted TMEM16A, in a manner similar to what was reported for th

173 ivity of Ca(2+)-activated chloride channels (TMEM16A), including the cystic fibrosis transmembrane co

174 ional.Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhance

175 e constructs) abrogated the growth effect of TMEM16A, indicating a role for mitogen-activated protein

176 Mechanistically, TMEM16A-induced cancer cell proliferation and tumor grow

177 gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric e

178 ent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabo

179 ES, and that this is blocked by the specific TMEM16A inhibitor T16inh-A01.

180 rast to the airway and intestinal cells, all TMEM16A inhibitors fully blocked CaCC current in salivar

181 TMEM16A inhibitors have been proposed for treatment of d

182 our novel chemical classes of small molecule TMEM16A inhibitors that fully blocked TMEM16A chloride c

183 osed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithe

184 ed the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry

185 iate TMEM16A activity, suggesting that CLCA1-TMEM16A interactions are Mg(2+)- and metal ion-dependent

186 that the calcium-activated chloride channel TMEM16A is a biomarker for pancreatic cancer with a poor

187 The calcium-activated chloride channel TMEM16A is a member of a conserved protein family that c

188 We conclude that ANO1/TMEM16A is a significant pathway in pancreatic acinar ce

189 In the gastrointestinal (GI) tract, TMEM16A is absent from smooth muscle cells, but present

190 physiological pH, E623 is un-protonated and TMEM16A is activated when intracellular calcium increase

191 gative HNSCC and that this overexpression of TMEM16A is associated with decreased patient survival.

192 demonstrate that the ion-conducting pore of TMEM16A is constituted of two functionally distinct modu

193 In addition, TMEM16A is expressed in airway smooth muscle cells and t

194 ed calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithel

195 CaCCs, we further show that TMEM16B but not TMEM16A is important for hippocampal CaCC, laying the gr

196 Here, we show that TMEM16A is located in the apical membranes of epithelial

197 ports suggest that the Ca(2+) sensitivity of TMEM16A is mediated by its association with calmodulin,

198 To test whether TMEM16A is necessary and sufficient to form functional C

199 Our results demonstrate that purified TMEM16A is necessary and sufficient to recapitulate the

200 TMEM16A is opened by voltage-dependent calcium binding a

201 The calcium-activated chloride channel TMEM16A is overexpressed in a variety of cancers, includ

202 Here, we demonstrate that TMEM16A is preferentially overexpressed in HPV-negative

203 In vitro, TMEM16A is required for EGF-induced store-operated calci

204 ciliogenesis and chloride transport by ANO1/TMEM16A is required for the genesis or maintenance of pr

205 TMEM16A is shown to be essential for proper activation a

206 Based on these results, we propose that TMEM16A is the major constituent of the vascular calcium

207 n, mouse, and rat BECs provide evidence that TMEM16A is the operative channel and contributes to Ca(2

208 The physiological importance of TMEM16A is underscored by the diminished rhythmic contra

209 TMEM16A is up-regulated in 75% of cases of pancreatic ca

210 ANO1 (TMEM16A) is a Ca(2+)-activated Cl(-) channel (CaCC) expr

211 ANO1 (TMEM16A) is a Ca(2+)-activated Cl(-) channel that regula

212 smembrane proteins with unknown function 16 (TMEM16A) is a calcium-activated chloride channel (CaCC)

213 Anoctamin-1 (ANO1, TMEM16A) is a principal CaCC subunit in many cell types,

214 Transmembrane member 16A (TMEM16A) is a widely expressed Ca(2+)-activated Cl(-) ch

215 ecome possible with the discovery that Ano1 (TMEM16a) is an essential subunit of CaCCs.

216 activated Cl ((-)) channel anoctamin-1 (ANO1/TMEM16A) is located in the primary cilium and that block

217 TMEM16A knockdown reduced intravascular pressure-induced

218 denced by the absence of immunoreactivity in TMEM16A knockout mice.

219 ic contraction of gastric smooth muscle from TMEM16A knockout mice.

220 analogous lysine mutation to TMEM16F-F518 in TMEM16A (L543K) is sufficient to confer CaPLSase activit

221 es and lipid peroxidation strongly activated TMEM16A, leading to depletion of calcium ion stores and

222 A1 constructs containing the VWA domain, and TMEM16A-like currents were activated.

223 Genetic deletion of TMEM16A markedly reduces the spontaneous activity of IHC

224 ator, Cl(-) channel in BECs and suggest that TMEM16A may be a potential target to modulate bile forma

225 lopment of small-molecule inhibitors against TMEM16A may be clinically relevant for treatment of huma

226 We demonstrate that TMEM16A-mediated control of cytoplasmic Cl(-) regulates

227 ctivated protein kinase (MAPK) activation in TMEM16A-mediated proliferation.

228 Importantly, the residual CaCC activity in Tmem16a(-/-) mice appeared inadequate for normal airway

229 trast, submandibular gland acinar cells from Tmem16A(-/-) mice lacked a Ca(2+)-activated Cl(-) curren

230 Best2(-/-) and Tmem16A(-/-) mice were used to further characterize the

231 VWA-dependent TMEM16A modulation was not modified by the S357N mutatio

232 of CaCCs, but was associated with increased TMEM16A mRNA and protein expression.

233 TMEM16A mRNA was identified in rat and human pulmonary a

234 Furthermore, TMEM16A mutant channels containing double cysteine subst

235 e that the cartilage ring defect observed in Tmem16a mutants is secondary to an expansion of the embr

236 dorsal aspect of the trachea was abnormal in Tmem16a mutants.

237 or of the calcium-activated chloride channel TMEM16A, N-((4-methoxy)-2-naphthyl)-5-nitroanthranilic a

238 Having identified TMEM16A of the transmembrane proteins with unknown funct

239 Direct pharmacological activation of TMEM16A offers a potential therapeutic strategy to reduc

240 ther, our data suggest that CLCA1 stabilizes TMEM16A on the cell surface, thus increasing surface exp

241 r binding experiments indicate CLCA1 engages TMEM16A on the surface of these cells.

242 ared; not only is Ca(2+) necessary to signal TMEM16a opening, but PIP(2) is also required.

243 We propose direct inhibition of TMEM16A or inhibition of lipid peroxidation as potential

244 93 cells transiently transfected with either TMEM16A or TMEM16B as well as from mouse parotid acinar

245 Heterologous expression of either TMEM16A or TMEM16B resulted in whole-cell anion currents

246 SMCs abolishes the effects of modulators for TMEM16A or VDCCs on a RyR-mediated rise in global [Ca(2+

247 Here we present evidence that TMEM16A (or anoctamin 1), a member of the transmembrane

248 s of TRPP1, TRPC1, TRPC3, TRPC6, TRPM4, ANO1/TMEM16A, or voltage-dependent Ca(2+) (CaV1.2) channels,

249 We found TMEM16A overexpression in 80% of head and neck squamous

250 TMEM16A overexpression significantly promoted anchorage-

251 Out data suggest that TMEM16A plays a general role in arteriolar and capillary

252 he calcium-activated chloride channel (CaCC) TMEM16A plays crucial roles in regulating neuronal excit

253 Cl(-) channel (CaCC), recently identified as TMEM16A, plays important roles in pulmonary vascular fun

254 TMEM16A potentiation is a novel approach for the treatme

255 ases.Objectives: To determine the effects of TMEM16A potentiation on epithelial fluid secretion and m

256 The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cel

257 polarized BEC monolayers with IL-4 increased TMEM16A protein expression, membrane localization, and t

258 TMEM16A protein levels on the cell surface were increase

259 e pore-loop of TMEM16F transplanted into the TMEM16A protein scaffold did not conduct anions or catio

260 TMEM16A in differentiated epithelial cells: TMEM16A provides a mechanism for enhanced ER Ca(2+) stor

261 INTS: The calcium-activated chloride channel TMEM16A provides a pathway for chloride ion movements th

262 Inhibition of TMEM16A reduced proliferation and fluid secretion in vit

263 Deleting 448 EAVK451 residues in TMEM16A reduced slow gating.

264 Our results reveal that TMEM16A regulation is more complicated than it initially

265 While opening of TMEM16A requires binding of intracellular Ca(2+), prolon

266 age-independent growth in vitro, and loss of TMEM16A resulted in inhibition of tumor growth both in v

267 TMEM16A RNAi knockdown also inhibited mainly the transie

268 CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and

269 External glutamic acid 623 (E623) is key for TMEM16A's ability to respond to external protons.

270 Collectively, TMEM16A serves as a transducer of vasoactive stimuli to

271 currents were significantly knocked down by TMEM16A siRNA.

272 Further analyses revealed that several TMEM16A splice variants were detected in rat PASMCs and

273 ogical functions, knowledge of the mammalian TMEM16A structure and identification of its pore-lining

274 ium-activated chloride channels that contain TMEM16A subunits.

275 a developmental small-molecule inhibitor of TMEM16A, T16A-inh01 (A01), abrogated tumor cell prolifer

276 activated calcium-dependent chloride channel TMEM16A (TAOS2 or ANO1) has been reported in several mal

277 Small-molecule, TMEM16A-targeted activators may be useful for drug thera

278 levels of the Ca(2+)-activated Cl(-) channel TMEM16A, the major apical Cl(-) efflux pathway in saliva

279 By contrast, expression of TMEM16A, the water channel aquaporin 5 (AQP5), and other

280 In TMEM16A this region has also been suggested to contain r

281 ice homozygous for a null allele of Tmem16a (Tmem16a(tm1Bdh)(/tm1Bdh)) and did not develop subsequent

282 eonatal mice homozygous for a null allele of Tmem16a (Tmem16a(-/-)) to investigate the role of this c

283 irth in mice homozygous for a null allele of Tmem16a (Tmem16a(tm1Bdh)(/tm1Bdh)) and did not develop s

284 ly includes Ca(2+)-activated anion channels (TMEM16A, TMEM16B), a cation channel (TMEM16F) and protei

285 cal tools to investigate the contribution of TMEM16A to CaCC conductance in human airway and intestin

286 ice homozygous for a null allele of Tmem16a (Tmem16a(-/-)) to investigate the role of this channel in

287 When compared with wild-type tracheas, the Tmem16a(-/-) tracheas exhibited a >60% reduction in puri

288 adequate for normal airway hydration because Tmem16a(-/-) tracheas exhibited significant, neonatal, l

289 GI muscles express splice variants of the Tmem16a transcript in addition to other paralogues of th

290 TMEM16A up-regulation is associated with the ligand-depe

291 used by a global rise in [Ca(2+)]i via a RyR-TMEM16A-VDCC signalling module sets the basal tone.

292 TMEM16A was found recently to be a calcium-activated Cl(

293 alcium-dependent chloride channel DOG1 (ANO1/TMEM16A), which is strongly and specifically expressed i

294 ic analysis of the tumorigenic properties of TMEM16A, which represents a potentially novel therapeuti

295 lass of CaCC, anoctamin 1 (ANO1), encoded by Tmem16a, which was discovered to be highly expressed in

296 d Main Results: Potentiating the activity of TMEM16A with ETX001 increased the Ca(2+)-activated Cl(-)

297 Our results also show that association of TMEM16A with other proteins, such as calmodulin, is not

298 Replacement of the putative pore-loop of TMEM16A with that of TMEM16B (TMEM16A-B channels) reduce

299 ns identified tannic acid as an inhibitor of TMEM16A, with IC(50) approximately 6 muM and approximate

300 conditions determine the open probability of TMEM16A without changing its calcium sensitivity.