Modulation of the voltage-gated potassium channel Kv2.1 by the anti-tumor alkylphospholipid perifosine

Delgado-Ramírez, Mayra; Morán-Zendejas, Rita; Aréchiga-Figueroa, Iván A.; Toro-Castillo, Carmen; Ramírez-Martínez, Juan F.; Rodríguez-Menchaca, Aldo A.

doi:10.1016/j.pharep.2015.11.006

Cited by 6 publications

(4 citation statements)

References 20 publications

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“…Transitions between these three states (gating) of Kv channels can be modulated by different stimuli. For instance, phosphorylation 3 , SUMOylation 4 , 5 polyunsaturated fatty acids 6 , accessory subunits 7 and different natural and synthetic compounds 8 , 9 , are well known modulators of Kv channel gating. Phosphoinositides, particularly phosphatidylinositol 4,5-bisphosphate (PIP 2 ), have also been shown to modulate the gating mechanism of several Kv channels 10 – 12 , although, some of these results have been debated 13 , 14 .…”

Section: Introductionmentioning

confidence: 99%

Regulation of Kv2.1 channel inactivation by phosphatidylinositol 4,5-bisphosphate

Delgado-Ramírez

Jesús-Pérez

Aréchiga-Figueroa

et al. 2018

Sci Rep

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Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is a membrane phospholipid that regulates the function of multiple ion channels, including some members of the voltage-gated potassium (Kv) channel superfamily. The PIP 2 sensitivity of Kv channels is well established for all five members of the Kv7 family and for Kv1.2 channels; however, regulation of other Kv channels by PIP 2 remains unclear. Here, we investigate the effects of PIP 2 on Kv2.1 channels by applying exogenous PIP 2 to the cytoplasmic face of excised membrane patches, activating muscarinic receptors (M1R), or depleting endogenous PIP 2 using a rapamycin-translocated 5-phosphatase (FKBP-Inp54p). Exogenous PIP 2 rescued Kv2.1 channels from rundown and partially prevented the shift in the voltage-dependence of inactivation observed in inside-out patch recordings. Native PIP 2 depletion by the recruitment of FKBP-Insp54P or M1R activation in whole-cell experiments, induced a shift in the voltage-dependence of inactivation, an acceleration of the closed-state inactivation, and a delayed recovery of channels from inactivation. No significant effects were observed on the activation mechanism by any of these treatments. Our data can be modeled by a 13-state allosteric model that takes into account that PIP 2 depletion facilitates inactivation of Kv2.1. We propose that PIP 2 regulates Kv2.1 channels by interfering with the inactivation mechanism.

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Section: Introductionmentioning

confidence: 99%

Regulation of Kv2.1 channel inactivation by phosphatidylinositol 4,5-bisphosphate

Delgado-Ramírez

Jesús-Pérez

Aréchiga-Figueroa

et al. 2018

Sci Rep

Self Cite

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“…Most studies have focused on the function of K v channels in viability of tumor cells, particularly tumor cells of epithelial origin, such as human mammary epithelial cell ( 2 , 3 ). Accumulated evidence indicated that the expression of K v channels is related to tumor development ( 4 ). However, the mechanism of K v channels in these cells is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Caveolin‑1 facilitated KCNA5 expression, promoting breast cancer viability

Sun

Liu

et al. 2018

Oncol Lett

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Potassium voltage-gated channel subfamily A member 5 (KCNA5) is a voltage-gated potassium channel protein encoded by the KCNA5 gene. A large number of studies have shown that KCNA5 is associated with the survival of malignant tumors, including breast cancer, but the detailed mechanism remains inconclusive. Our previous study found that KCNA5 is co-expressed with a scaffolding protein, caveolin-1 in MCF-10A-neoT non-tumorigenic epithelial cell. In the present study, KCNA5 and caveolin-1 were expressed in breast cancer tissues and cell lines. Exposing MCF-10A-neoT to 2 mM of methyl-β-cyclodextrin, an agent to disrupt caveolae and lipid rafts led to a downregulation of caveolin-1 that reduced the expression of KCNA5. Furthermore, following caveolin-1 knockdown, the expression of KCNA5 was decreased in MDA-MB-231 human breast cancer and MCF-10A-neoT non-tumorigenic epithelial cell lines. In subsequent experiments, the MTT assay showed that increased caveolin-1 and KCNA5 expression promoted the survival of MCF-7 human breast cancer cells, but cell survival was not affected following KCNA5 overexpression alone. Using small interfering RNA technology, KCNA5-silenced MCF-10A-neoT cells were established and a decreased level of phosphorylated-AKT serine/threonine kinase (AKT) was observed in the cells compared with the parental cells. Overall, these results suggested that caveolin-1 facilitated KCNA5 expression and may be associated with AKT activation.

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“…As we will explain later, Kv2.1 exhibits a cell cycle-dependent subcellular distribution, concentrating in raft-like lipid domains during M phase [49]. Thus, anti-neoplastic treatments targeting lipid rafts affect Kv2.1 function [50].…”

Section: Kv Channels and Cancermentioning

confidence: 99%

Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation

Serrano-Novillo

Capera

Colomer-Molera

et al. 2019

Cancers

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Voltage-gated potassium channels (Kv) are the largest group of ion channels. Kv are involved in controlling the resting potential and action potential duration in the heart and brain. Additionally, these proteins participate in cell cycle progression as well as in several other important features in mammalian cell physiology, such as activation, differentiation, apoptosis, and cell volume control. Therefore, Kv remarkably participate in the cell function by balancing responses. The implication of Kv in physiological and pathophysiological cell growth is the subject of study, as Kv are proposed as therapeutic targets for tumor regression. Though it is widely accepted that Kv channels control proliferation by allowing cell cycle progression, their role is controversial. Kv expression is altered in many cancers, and their participation, as well as their use as tumor markers, is worthy of effort. There is an ever-growing list of Kv that remodel during tumorigenesis. This review focuses on the actual knowledge of Kv channel expression and their relationship with neoplastic proliferation. In this work, we provide an update of what is currently known about these proteins, thereby paving the way for a more precise understanding of the participation of Kv during cancer development.

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Modulation of the voltage-gated potassium channel Kv2.1 by the anti-tumor alkylphospholipid perifosine

Abstract: Taken together, these results show that perifosine modified the Kv2.1 inactivation gating resulting in a decrease of the current amplitude. These data will help to elucidate the mechanism of action of this promising anti-cancer drug on ion channels and their possible implications.

Cited by 6 publications

References 20 publications

Regulation of Kv2.1 channel inactivation by phosphatidylinositol 4,5-bisphosphate

Regulation of Kv2.1 channel inactivation by phosphatidylinositol 4,5-bisphosphate

Caveolin‑1 facilitated KCNA5 expression, promoting breast cancer viability

Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation

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