Coupling of TRPV6 and TMEM16A in epithelial principal cells of the rat epididymis

Gao, Da Yuan; Zhang, Bao Li; Leung, Mkh; Au, Simon C.L.; Wong, Patrick; Shum, Winnie

doi:10.1085/jgp.201611626

Cited by 26 publications

(24 citation statements)

References 58 publications

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“…TMEM16A couples to different Ca 2+ -permeable ion channels that are predominantly expressed in different cells. For example, TMEM16A has been found to be activated by Ca 2+ influx via TRPV1 in mouse dorsal root ganglion neurons [ 28 ], TRPV4 in the choroid plexus [ 126 ], TRPV6 in epithelial principal cells of the rat epididymis [ 127 ], TRPC1 in salivary gland cells [ 128 ], TRPC2 in rat thyroid cells [ 129 ], TRPC6 in cerebral artery myocytes [ 130 ], Cav1.4 at the photoreceptor ribbon synapse [ 131 ], Cav1.2 in canine ventricular myocytes [ 132 ], and store-operated Ca 2+ entry in eccrine sweat glands [ 133 ]. Therefore, TMEM16A is activated by Ca 2+ via different Ca 2+ -permeable ion channels in a cell-specific manner.…”

Section: Discussionmentioning

confidence: 99%

Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

et al. 2017

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TMEM16A (known as anoctamin 1) Ca2+-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.

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Section: Discussionmentioning

confidence: 99%

Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

et al. 2017

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“…Although detailed mechanisms are currently not fully understood, it is clear that also other anoctamins affect [Ca 2+ ] i , i.e., basal [Ca 2+ ] i as well as receptor mediated Ca 2+ signals depend on expression of anoctamins [110]. Apart from compartmentalization, protein interaction [163] and membrane depolarization, anoctamins may also contribute to cell proliferation and cell growth by operating as counter-ion channels. Counter ion movement of K + or Cl − over the ER membrane is necessary for charge compensation to allow for efficient Ca 2+ transport out of the ER via release channels, and for re-uptake of Ca 2+ into the ER by the sarcoplasmic endoplasmic reticulum Ca 2+ -ATPase (SERCA) [164,165].…”

Section: Anoctamins Control Intracellular Ca2+ Levelsmentioning

confidence: 99%

Contribution of Anoctamins to Cell Survival and Cell Death

Kunzelmann

Ousingsawat

Benedetto

et al. 2019

Cancers

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Before anoctamins (TMEM16 proteins) were identified as a family of Ca2+-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca2+ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca2+i levels near the plasma membrane, and/or by controlling the intracellular Cl− concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis.

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“…Thus, TMEM16A-positive epididymal cells could indicate ICCs (Huang et al 2009). Most recently, TMEM16 was suggested to be also functionally active in epididymal epithelial cells (Gao et al 2016). In these cells, TMEMA16 is coupled to the Ca 2+ channel TRPV6.…”

Section: Influence Of Elements Of the Smc Layer On Contractions Of Thmentioning

confidence: 99%

Contractility of the epididymal duct - function, regulation and potential drug effects

et al. 2018

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During their transit through the epididymis, spermatozoa mature and acquire motility and fertilizing capacity. The smooth muscle cells (SMCs) of the epididymal duct are thought to be responsible for the adequate transport of spermatozoa. Thus, precise regulation of SMC function also represents a prerequisite for sperm maturation thereby contributing to male fertility. In this review we would like to highlight various aspects of epididymal SMC function and discuss several angles with respect to regulation of contraction and relaxation. Different to the vas deferens, where disturbed SMC pathways resulting in male infertility could be defined, comparable information is missing in the epididymis. We therefore include some vas deferens data which could also be useful for a better understanding of epididymal SMC function. Furthermore, we would like to draw attention to drugs used in clinical practice and their potential (side) effects on contractions in the epididymis.

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Coupling of TRPV6 and TMEM16A in epithelial principal cells of the rat epididymis

Cited by 26 publications

References 58 publications

Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

Contribution of Anoctamins to Cell Survival and Cell Death

Contractility of the epididymal duct - function, regulation and potential drug effects

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