The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
TMEM16A Inhibitors Reveal TMEM16A as a Minor Component of Calcium-activated Chloride Channel Conductance in Airway and Intestinal Epithelial Cells
Open accessAbstract
TMEM16A (ANO1) functions as a calcium-activated chloride channel (CaCC). We developed pharmacological tools to investigate the contribution of TMEM16A to CaCC conductance in human airway and intestinal epithelial cells. A screen of ∼110,000 compounds revealed four novel chemical classes of small molecule TMEM16A inhibitors that fully blocked TMEM16A chloride current with an IC(50) < 10 μM, without interfering with calcium signaling. Following structure-activity analysis, the most potent inhibitor, an aminophenylthiazole (T16A(inh)-A01), had an IC(50) of ∼1 μM. Two distinct types of inhibitors were identified. Some compounds, such as tannic acid and the arylaminothiophene CaCC(inh)-A01, fully inhibited CaCC current in human bronchial and intestinal cells. Other compounds, including T16A(inh)-A01 and digallic acid, inhibited total CaCC current in these cells poorly, but blocked mainly an initial, agonist-stimulated transient chloride current. TMEM16A RNAi knockdown also inhibited mainly the transient chloride current. In contrast to the airway and intestinal cells, all TMEM16A inhibitors fully blocked CaCC current in salivary gland cells. We conclude that TMEM16A carries nearly all CaCC current in salivary gland epithelium, but is a minor contributor to total CaCC current in airway and intestinal epithelia. The small molecule inhibitors identified here permit pharmacological dissection of TMEM16A/CaCC function and are potential development candidates for drug therapy of hypertension, pain, diarrhea, and excessive mucus production.
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Cites
TMEM16A confers receptor-activated calcium-dependent chloride conductance
Yang, Y. D., Cho, H., Koo, J. Y., Tak, M. H., Cho, Y., Shim, W.-S., Park, S. P., Lee, J., Lee, B., Kim, B.-M., et al. (2008) · Nature · doi:10.1038/nature07313 · Cited by 1,283
TMEM16A, A Membrane Protein Associated with Calcium-Dependent Chloride Channel Activity
Caputo, A., Caci, E., Ferrera, L., Pedemonte, N., Barsanti, C., Sondo, E., Pfeffer, U., Ravazzolo, R., Zegarra-Moran, O., & Galietta, L. J. V. (2008) · Science · doi:10.1126/science.1163518 · Cited by 1,263
Expression Cloning of TMEM16A as a Calcium-Activated Chloride Channel Subunit
Schroeder, B. C., Cheng, T., Jan, Y. N., & Jan, L. Y. (2008) · Cell · doi:10.1016/j.cell.2008.09.003 · Cited by 1,148
Ma, T., Thiagarajah, J. R., Yang, H., Sonawane, N. D., Folli, C., Galietta, L. J. V., & Verkman, A. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16112 · Cited by 633
Self-citationCALCIUM-ACTIVATED CHLORIDE CHANNELS
Hartzell, C., Putzier, I., & Arreola, J. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.67.032003.154341 · Cited by 626
Ma, T., Thiagarajah, J. R., Yang, H., Sonawane, N. D., Folli, C., Galietta, L. J. V., & Verkman, A. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0216112 · Cited by 536
Self-citationChloride channels as drug targets
Verkman, A. S., & Galietta, L. J. V. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2780 · Cited by 469
Self-citationHwang, S. J., Blair, P. J. A., Britton, F. C., O’Driscoll, K. E., Hennig, G., Bayguinov, Y. R., Rock, J. R., Harfe, B. D., Sanders, K. M., & Ward, S. M. (2009) · The Journal of Physiology · doi:10.1113/jphysiol.2009.176198 · Cited by 418
Pathogenesis of Intestinal and Systemic Rotavirus Infection
Ramig, R. F. (2004) · Journal of Virology · doi:10.1128/jvi.78.19.10213-10220.2004 · Cited by 377
Studies on expression and function of the TMEM16A calcium-activated chloride channel
Huang, F., Rock, J. R., Harfe, B. D., Cheng, T., Huang, X., Jan, Y. N., & Jan, L. Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911935106 · Cited by 310
Cited by
Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease
Hegyi, P., Maléth, J., Walters, J. R., Hofmann, A. F., & Keely, S. J. (2018) · Physiological Reviews · doi:10.1152/physrev.00054.2017 · Cited by 269
Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte
Twyffels, L., Strickaert, A., Virreira, M., Massart, C., Van Sande, J., Wauquier, C., Beauwens, R., Dumont, J. E., Galietta, L. J., Boom, A., et al. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00126.2014 · Cited by 77
Haggie, P. M., Cil, O., Lee, S., Tan, J.-A., Rivera, A. A., Phuan, P.-W., & Verkman, A. S. (2018) · JCI Insight · doi:10.1172/jci.insight.121370 · Cited by 56
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Metadata
- Authors
- Namkung, W., Phuan, P.-W., & Verkman, A. S.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 286
- Issue
- 3
- Pages
- 2365-2374
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2065417952
- Cited by
- 353
- References
- 25
- FWCI
- 8.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
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