The Prognostic Value and Mechanisms of TMEM16A in Human Cancer

Chen, Wenjian; Gu, Meng; Gao, Chaobing; Chen, Bangjie; Yang, Jun; Xie, Xiaoli; Wang, Xinyi; Sun, Jun; Wang, Jinian

doi:10.3389/fmolb.2021.542156

Cited by 7 publications

(8 citation statements)

References 126 publications

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“…TMEM16 proteins have emerged as important pharmacological targets for the treatment of cancer, asthma and more recently COVID-19 22 – 25 , 41 (clinicaltrials.gov). Our data indicate that niclosamide and 1PBC bind the same binding pocket in TMEM16F (Fig.…”

Section: Discussionmentioning

confidence: 99%

Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase

Feng,

Puchades,

et al. 2023

Nat Commun

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The dual functions of TMEM16F as Ca2+-activated ion channel and lipid scramblase raise intriguing questions regarding their molecular basis. Intrigued by the ability of the FDA-approved drug niclosamide to inhibit TMEM16F-dependent syncytia formation induced by SARS-CoV-2, we examined cryo-EM structures of TMEM16F with or without bound niclosamide or 1PBC, a known blocker of TMEM16A Ca2+-activated Cl- channel. Here, we report evidence for a lipid scrambling pathway along a groove harboring a lipid trail outside the ion permeation pore. This groove contains the binding pocket for niclosamide and 1PBC. Mutations of two residues in this groove specifically affect lipid scrambling. Whereas mutations of some residues in the binding pocket of niclosamide and 1PBC reduce their inhibition of TMEM16F-mediated Ca2+ influx and PS exposure, other mutations preferentially affect the ability of niclosamide and/or 1PBC to inhibit TMEM16F-mediated PS exposure, providing further support for separate pathways for ion permeation and lipid scrambling.

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Section: Discussionmentioning

confidence: 99%

Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase

Feng,

Puchades,

et al. 2023

Nat Commun

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“…TMEM16 proteins have emerged as important pharmacological targets for the treatment of cancer, asthma and more recently COVID-19 (12,13) (26) (clinicaltrials.gov). Our data indicate that niclosamide and 1PBC bind the same, conserved site in both TMEM16A and TMEM16F (Fig.…”

Section: Discussionmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

“…Through its lipid scrambling activity, TMEM16F allows diverse lipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), to passively move between the inner and outer lea ets of the plasma membrane (1, 2, 6,7,10,11). Both TMEM16A and TMEM16F play critical roles in numerous physiological processes and have emerged as important targets for therapeutic intervention in multiple diseases, including cancer, asthma, and in particular 2,12,13).TMEM16A is required for airway and secretory gland secretion (1, 2). Notably, a TMEM16A activator is under consideration for the treatment of cystic brosis ( 14), whereas TMEM16A inhibitors with potent bronchodilator activities are being tested as anti-asthma drugs (15, 16).…”

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confidence: 99%

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Identification of a conserved drug binding pocket in TMEM16 proteins

Cheng

Feng

Puchades

et al. 2022

Preprint

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The TMEM16 family of calcium-activated membrane proteins includes ten mammalian paralogs (TMEM16A-K) playing distinct physiological roles with some implicated in cancer and airway diseases. Their modulators with therapeutic potential include 1PBC, a potent inhibitor with anti-tumoral properties, and the FDA-approved drug niclosamide that targets TMEM16F to inhibit syncytia formation induced by SARS-CoV-2 infection. Here, we report cryo-EM structures of TMEM16F associated with 1PBC and niclosamide, revealing that both molecules bind the same drug binding pocket. We functionally and computationally validate this binding pocket in TMEM16A as well as TMEM16F, thereby showing that drug modulation also involves residues that are not conserved between TMEM16A and TMEM16F. This study establishes a much-needed structural framework for the development of more potent and more specific drug molecules targeting TMEM16 proteins.

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“…In addition, the overexpression of TMEM16A has been found in various cancers and may have potential as an emergent target of drug discovery. 197,198) Traditional Cl − channel blockers, including niflumic acid and anthracene-9-carboxcylic acid, exhibit low selectivity to TMEM16A channels. The BK channel activators NS1619 and isopimaric acid augmented TMEM16A channels as well, 168) indicating the overlap of channel opening effects.…”

Section: -1 Bk Channel-related Diseases and Modulator Pharmacologymentioning

confidence: 99%

Reciprocal Relationship between Ca<sup>2+</sup> Signaling and Ca<sup>2+</sup>-Gated Ion Channels as a Potential Target for Drug Discovery

Imaizumi

2022

Biological & Pharmaceutical Bulletin

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Cellular Ca 2 signaling functions as one of the most common second messengers of various signal transduction pathways in cells and mediates a number of physiological roles in a cell-type dependent manner. Ca 2 signaling also regulates more general and fundamental cellular activities, including cell proliferation and apoptosis. Among ion channels, Ca 2 -permeable channels in the plasma membrane as well as endo-and sarcoplasmic reticulum membranes play important roles in Ca 2 signaling by directly contributing to the influx of Ca 2 from extracellular spaces or its release from storage sites, respectively. Furthermore, Ca 2 -gated ion channels in the plasma membrane often crosstalk reciprocally with Ca 2 signals and are central to the regulation of cellular functions. This review focuses on the physiological and pharmacological impact of i) Ca 2 -gated ion channels as an apparatus for the conversion of cellular Ca 2 signals to intercellularly propagative electrical signals and ii) the opposite feedback regulation of Ca 2 signaling by Ca 2 -gated ion channel activities in excitable and non-excitable cells.Key words Ca 2+ signaling; Ca 2+ microdomain; ion channel; Ca 2+ permeable channel; Ca 2+ -activated K + channel; Ca 2+ -activated Cl − channel 2-1. Ca 2+ -Gated Ion Channels The established classification and nomenclature of ion channels need to be referred to those presented by The International Union of Basic and Clinical Pharmacology (IUPHAR) (https://www.guideto pharmacology.org/). 3) One of the practical classifications of ion channels may be that based on gating mechanisms. Table 1 proposes a classification of ion channels on the PM based on their gating mechanisms. RyRs and IP 3 Rs are channels in ER/SR membranes, but are also listed here because of their close involvement in the issues discussed in this review.In this classification, "Ca 2+ -gated ion channels" refer to channels for which an increase in [Ca 2+ ] i is an essential factor for their activation. The Ca 2+ -gated K + channel family consists of three subfamilies classified by channel conduc-

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The Prognostic Value and Mechanisms of TMEM16A in Human Cancer

Cited by 7 publications

References 126 publications

Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase

Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase

Identification of a conserved drug binding pocket in TMEM16 proteins

Reciprocal Relationship between Ca<sup>2+</sup> Signaling and Ca<sup>2+</sup>-Gated Ion Channels as a Potential Target for Drug Discovery

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