Calmodulin-Dependent Regulation of Overexpressed but Not Endogenous TMEM16A Expressed in Airway Epithelial Cells

Talbi, Khaoula; Ousingsawat, Jiraporn; Centeio, Raquel; Schreiber, Rainer; Kunzelmann, Karl

doi:10.3390/membranes11090723

Cited by 6 publications

(3 citation statements)

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“…Overexpression of K Ca 3.1 in HEK-293 cells, which normally do not express K Ca 3.1 [ 52 ], significantly increased their sensitivity to mitoTRAM-34 and rev -mitoTRAM (Fig. 3f ).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

et al. 2022

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Ion channels are non-conventional, druggable oncological targets. The intermediate-conductance calcium-dependent potassium channel (KCa3.1) is highly expressed in the plasma membrane and in the inner mitochondrial membrane (mitoKCa3.1) of various cancer cell lines. The role mitoKCa3.1 plays in cancer cells is still undefined. Here we report the synthesis and characterization of two mitochondria-targeted novel derivatives of a high-affinity KCa3.1 antagonist, TRAM-34, which retain the ability to block channel activity. The effects of these drugs were tested in melanoma, pancreatic ductal adenocarcinoma and breast cancer lines, as well as in vivo in two orthotopic models. We show that the mitochondria-targeted TRAM-34 derivatives induce release of mitochondrial reactive oxygen species, rapid depolarization of the mitochondrial membrane, fragmentation of the mitochondrial network. They trigger cancer cell death with an EC50 in the µM range, depending on channel expression. In contrast, inhibition of the plasma membrane KCa3.1 by membrane-impermeant Maurotoxin is without effect, indicating a specific role of mitoKCa3.1 in determining cell fate. At sub-lethal concentrations, pharmacological targeting of mitoKCa3.1 significantly reduced cancer cell migration by enhancing production of mitochondrial reactive oxygen species and nuclear factor-κB (NF-κB) activation, and by downregulating expression of Bcl-2 Nineteen kD-Interacting Protein (BNIP-3) and of Rho GTPase CDC-42. This signaling cascade finally leads to cytoskeletal reorganization and impaired migration. Overexpression of BNIP-3 or pharmacological modulation of NF-κB and CDC-42 prevented the migration-reducing effect of mitoTRAM-34. In orthotopic models of melanoma and pancreatic ductal adenocarcinoma, the tumors at sacrifice were 60% smaller in treated versus untreated animals. Metastasis of melanoma cells to lymph nodes was also drastically reduced. No signs of toxicity were observed. In summary, our results identify mitochondrial KCa3.1 as an unexpected player in cancer cell migration and show that its pharmacological targeting is efficient against both tumor growth and metastatic spread in vivo.

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“…Overexpression of K Ca 3.1 in HEK-293 cells, which normally do not express K Ca 3.1 [ 52 ], significantly increased their sensitivity to mitoTRAM-34 and rev -mitoTRAM (Fig. 3f ).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

et al. 2022

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“…Magnesium binding to TMEM proteins could involve a magnesium-calcium competition similar to some other calcium-dependent proteins often involving the regulatory protein calmodulin [79]. A direct interaction between TMEM proteins and calmodulin has been suggested but is still controversial [80].…”

Section: Magnesium Cognition and The Erythrocytementioning

confidence: 99%

Erythrocytes as Messengers for Information and Energy Exchange between Cells

Johansson¹,

Falk²

2023

The Erythrocyte - A Unique Cell

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Evolution has created a hierarchy of systems for information and energy using different cells according to messages generated from DNA, RNA, and other sources. Erythrocytes are formed in high speed at about 2 × 106/s to balance dying or not working erythrocytes to maintain optimal energy and information transfer. Important information is handled by nucleotides and distribution of metal ions and phosphates when starting synthesis process. Handling of these processes needs kinases known to be magnesium-dependent. Oxygen delivered by erythrocytes is used by other cells to synthesize ATP and to increase reaction capacity. Complex signals to bone marrow balance erythroblasts before developing into reticulocytes and erythrocytes. We discuss some aspects of erythrocyte communication with other cells of the body with special focus on magnesium and selenium in this process.

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“…A total of five contributions are included, namely three articles and two reviews. In their article Talbi et al [1] provided insightful data on the regulation of the chloride channel TMEM16A by Ca 2+ /calmodulin (CAM). In TMEM16A-overexpressing HEK293 cells, Ca 2+ sensitivity of the chloride channel evidently was modulated by interaction with CAM resulting in an increase in sensitivity.…”

mentioning

confidence: 99%