Function and Regulation of the Calcium-Activated Chloride Channel Anoctamin 1 (TMEM16A)

Arreola, Jorge; Pérez‐Cornejo, Patricia; Segura-Covarrubias, Guadalupe; Corral-Fernández, Nancy E.; León-Aparicio, Daniel; Guzmán-Hernández, María Luisa

doi:10.1007/164_2022_592

Cited by 8 publications

(7 citation statements)

References 282 publications

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“…As shown in Figure 3C , schisandrathera D did not inhibit forskolin-induced CFTR activity, whereas CFTR- inh 172, a selective CFTR inhibitor, inhibited CFTR-induced current. Since ANO1 is also activated by low calcium levels ( Arreola et al, 2022 ), we confirmed whether schisandrathera D had an effect on the ATP-mediated increase in intracellular calcium signaling. Since schisandrathera D had no effect on intracellular calcium levels at concentrations of up to 30 μM, it can be argued that schisandrathera D selectively inhibits ANO1.…”

Section: Resultssupporting

confidence: 69%

ANO1-downregulation induced by schisandrathera D: a novel therapeutic target for the treatment of prostate and oral cancers

et al. 2023

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Anoctamin 1 (ANO1), a drug target for various cancers, including prostate and oral cancers, is an intracellular calcium-activated chloride ion channel that plays various physiopathological roles, especially in the induction of cancer growth and metastasis. In this study, we tested a novel compound isolated from Schisandra sphenanthera, known as schisandrathera D, for its inhibitory effect on ANO1. Schisandrathera D dose-dependently suppressed the ANO1 activation-mediated decrease in fluorescence of yellow fluorescent protein; however, it did not affect the adenosine triphosphate-induced increase in the intracellular calcium concentration or forskolin-induced cystic fibrosis transmembrane conductance regulator activity. Specifically, schisandrathera D gradually decreased the levels of ANO1 protein and significantly reduced the cell viability in ANO1-expressing cells when compared to those in ANO1-knockout cells. These effects could be attributed to the fact that schisandrathera D displayed better binding capacity to ANO1 protein than the previously known ANO1 inhibitor, Ani9. Finally, schisandrathera D increased the levels of caspase-3 and cleaved poly (ADP-ribose) polymerase 1, thereby indicating that its anticancer effect is mediated through apoptosis. Thus, this study highlights that schisandrathera D, which reduces ANO1 protein levels, has apoptosis-mediated anticancer effects in prostate and oral cancers, and thus, can be further developed into an anticancer agent.

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Section: Resultssupporting

confidence: 69%

ANO1-downregulation induced by schisandrathera D: a novel therapeutic target for the treatment of prostate and oral cancers

et al. 2023

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“…Each pore is activated by voltage-dependent binding of two intracellular calcium ions to a high-affinity binding site. In addition, the binding of phosphatidylinositol 4,5-bisphosphate to sites scattered throughout the cytosolic side of the protein aids in calcium activation process ( Arreola et al, 2022 ). Moreover, Shi et al (2021) demonstrated that theaflavin plays an important role in the pore blockade of ANO1 through mutagenesis experiments and inhibits viability in lung adenocarcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a novel natural compound, vitekwangin B, with ANO1 protein reduction properties and anticancer potential

Seo,

Lee,

Kim

et al. 2024

Front. Pharmacol.

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Background: Prostate cancer and non-small cell lung cancer (NSCLC) present significant challenges in the development of effective therapeutic strategies. Hormone therapies for prostate cancer target androgen receptors and prostate-specific antigen markers. However, treatment options for prostatic small-cell neuroendocrine carcinoma are limited. NSCLC, on the other hand, is primarily treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors but exhibits resistance. This study explored a novel therapeutic approach by investigating the potential anticancer properties of vitekwangin B, a natural compound derived from Vitex trifolia.Methods: Vitekwangin B was chromatographically isolated from the fruits of V. trifolia. ANO1 protein levels in prostate cancer and NSCLC cells were verified and evaluated again after vitekwangin B treatment.Results: Vitekwangin B did not inhibit anoctamin1 (ANO1) channel function but significantly reduced ANO1 protein levels. These results demonstrate that vitekwangin B effectively inhibited cancer cell viability and induced apoptosis in prostate cancer and NSCLC cells. Moreover, it exhibited minimal toxicity to liver cells and did not affect hERG channel activity, making it a promising candidate for further development as an anticancer drug.Conclusion: Vitekwangin B may offer a new direction for cancer therapy by targeting ANO1 protein, potentially improving treatment outcomes in patients with prostate cancer and NSCLC. Further research is needed to explore its full potential and overcome existing drug resistance challenges.

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“…Rapamycin, which also binds to FKBP12 without inhibiting CaN and disrupts FKBP12 interactions, inhibits DNA synthesis and smooth muscle cell growth (Marx et al, 1995). As has been extensively researched, TMEM16A plays an essential role in vascular smooth muscle, where it helps to control blood pressure (for recent reviews, see (Arreola et al, 2024(Arreola et al, , 2022). Whether the inhibitory effect of rapamycin on smooth muscle is due to its ability to interrupt the interaction of FKBP12 with TMEM16A remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Fkbp12-Bound Calcineurin Control Tmem16a Activity

Guzmán-Hernández,

Huerta,

López-Romero

et al. 2024

Preprint

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The Ca2+-dependent Cl-channel TMEM16A activity is vital for mammals. Critical functions such as blood pressure, pain, fluid and electrolyte secretion, peristalsis, and electrical activity depend on TMEM16A Cl-fluxes. Ciclosporin A (CsA) and FK506, two immunosuppressants that inhibit calcineurin (CaN), down-regulate TMEM16A function. However, the underlying mechanism remains undetermined. CsA binds to cyclophilin 1, whereas FK506 binds to FKBP12, and both complexes subsequently inhibit CaN, a phosphatase that maintains TMEM16A function. Here, we show that TMEM16A-EGFP and mRFP-FKBP12 colocalize in HEK-AD293 cells stimulated with the Ca2+ionophore ionomycin, FKBP12 co-immunoprecipitated with TMEM16A expressed in CaN-depleted HEK-AD293 cells, ionomycin favoured TMEM16A and FKBP12 interaction in a bimolecular fluorescence complementation assay in live cells, and TMEM16A currents recorded from CaN-depleted HEK-AD293 cells were insensitive to CsA and FK506. These data support the idea that FKBP12 works as an auxiliary protein of TMEM16A, thus enabling the interaction of CaN under physiological conditions. This heteromerization is essential to sustain TMEM16A activity. On the contrary, disrupting the Ca2+-stimulated CaN-FKBP12-TMEM16A heterotrimer or inhibiting CaN with CsA or FK506 does not preclude TMEM16A activation but decreases activity.

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Function and Regulation of the Calcium-Activated Chloride Channel Anoctamin 1 (TMEM16A)

Cited by 8 publications

References 282 publications

ANO1-downregulation induced by schisandrathera D: a novel therapeutic target for the treatment of prostate and oral cancers

ANO1-downregulation induced by schisandrathera D: a novel therapeutic target for the treatment of prostate and oral cancers

Discovery of a novel natural compound, vitekwangin B, with ANO1 protein reduction properties and anticancer potential

Fkbp12-Bound Calcineurin Control Tmem16a Activity

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