An inhibitor of TMEM16A channels
Transmembrane protein 16A (TMEM16A, also known as anoctamin-1) is a calcium-activated chloride channel (CaCC) with roles in transepithelial anion transport and smooth muscle contraction. T16A(inh)-A01 is an aminophenylthiazole that inhibits transient TMEM16A-mediated chloride currents with an IC50 value of ~1 μM.[1],[2] Its inhibitory effects are independent of voltage and do not prolong the rate of TMEM16A current deactivation.[2]T16A(inh)-A01 blocks CaCC activity in vascular smooth muscle cells and relaxes mouse and human blood vessels.[3] It also inhibits the proliferation of pancreatic cancer and squamous carcinoma cells in culture.[4],[5]
Reference:
[1]. Namkung, W., Phuan, P.W., and Verkman, A.S. TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. The Journal of Biological Chemisty 286(3), 2365-2374 (2011).
[2]. Bradley, E., Fedigan, S., Webb, T., et al. Pharmacological characterization of TMEM16A currents. Channels 8(4), 308-320 (2014).
[3]. Davis, A.J., Shi, J., Pritchard, H.A.T., et al. Potent vasorelaxant activity of the TMEM16A inhibitor T16Ainh-A01. British Journal of Pharmacology 168, 773-784 (2013).
[4]. Mazzone, A., Eisenman, S.T., Strege, P.R., et al. Inhibition of cell proliferation by a selective inhibitor of the Ca2+ activated Cl- channel, Ano1. Biochemical and Biophysical Research Communications 427(2), 248-253 (2012).
[5]. Duvvuri, U., Shiwarski, D.J., Xiao, D., et al. TMEM16A induces MAPK and contributes directly to tumorigenesis and cancer progression. Cancer Research 72(13), 3270-3281 (2012).
| Cell experiment [1]: | |
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Cell lines |
Rabbit pulmonary artery myocytes |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
Whole cell IClCa were evoked by pipette solution which had the following composition (in mM): TEA (20), CsCl (106), HEPES-CsOH (10, pH 7.2), BAPTA (10), ATP.Mg (5) and GTP.diNa (0.2). To this solution, 7.08 mM CaCl2 were added to achieve a free [Ca2+] of 500 nM. The bathing solution had the following composition (in mM): NaCl (126), HEPES-NaOH (10, pH 7.35), TEA (8.4), glucose (20), MgCl2 (1.2) and CaCl2 (1.8). The effect of T16Ainh-A01 (1–30 μM) was studied on IClCa evoked by 500 nM free Ca2+. |
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Applications |
In rabbit pulmonary artery myocytes T16Ainh-A01 (1–30 μM) inhibited single calcium (Ca2+)-activated whole cell currents activated by 500 nM free Ca2+. |
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参考文献: [1] Alison J Davis, et al. Potent vasorelaxant activity of the TMEM16A inhibitor T16Ainh-A01. Br J Pharmacol. 2013 Feb; 168(3): 773–784. |
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