Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration

Robles-Martínez, Leticia; Garay, Edith; Martel-Gallegos, M. G.; Cisneros-Mejorado, Abraham; Pérez-Montiel, Delia; Lara, Amaranta Manrique de; Arellano, Rogelio O.

doi:10.1038/s41598-017-04292-6

Cited by 18 publications

(9 citation statements)

References 44 publications

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“…KCa3.1 has not been shown to couple to P2X4 in microglia but it has been shown to associate with the P2Y2 receptor. In ovarian cancer cells activation and opening of KCa3.1 channels induced by intracellular calcium release from internal stores caused by activation of P2Y2 receptors, significantly influences cellular motility (Robles-Martinez et al, 2017). In microglia, this P2Y2-KCa3.1 axis also regulates migration-following P2Y receptor activation by UTP, calcium influx through CRAC/Orai1 channels replenishes the depleted stores, and this is facilitated by KCa3.1 channel activity (Ferreira & Schlichter, 2013).…”

Section: P2x4 Expression Changes In Ischemic Stroke In Micementioning

confidence: 99%

Biophysical basis for Kv1.3 regulation of membrane potential changes induced by P2X4‐mediated calcium entry in microglia

Nguyen

Lucente

Chen

et al. 2020

Glia

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Microglia‐mediated inflammation exerts adverse effects in ischemic stroke and in neurodegenerative disorders such as Alzheimer's disease (AD). Expression of the voltage‐gated potassium channel Kv1.3 is required for microglia activation. Both genetic deletion and pharmacological inhibition of Kv1.3 are effective in reducing microglia activation and the associated inflammatory responses, as well as in improving neurological outcomes in animal models of AD and ischemic stroke. Here we sought to elucidate the molecular mechanisms underlying the therapeutic effects of Kv1.3 inhibition, which remain incompletely understood. Using a combination of whole‐cell voltage‐clamp electrophysiology and quantitative PCR (qPCR), we first characterized a stimulus‐dependent differential expression pattern for Kv1.3 and P2X4, a major ATP‐gated cationic channel, both in vitro and in vivo. We then demonstrated by whole‐cell current‐clamp experiments that Kv1.3 channels contribute not only to setting the resting membrane potential but also play an important role in counteracting excessive membrane potential changes evoked by depolarizing current injections. Similarly, the presence of Kv1.3 channels renders microglia more resistant to depolarization produced by ATP‐mediated P2X4 receptor activation. Inhibiting Kv1.3 channels with ShK‐223 completely nullified the ability of Kv1.3 to normalize membrane potential changes, resulting in excessive depolarization and reduced calcium transients through P2X4 receptors. Our report thus links Kv1.3 function to P2X4 receptor‐mediated signaling as one of the underlying mechanisms by which Kv1.3 blockade reduces microglia‐mediated inflammation. While we could confirm previously reported differences between males and females in microglial P2X4 expression, microglial Kv1.3 expression exhibited no gender differences in vitro or in vivo. Main Points The voltage‐gated K+ channel Kv1.3 regulates microglial membrane potential. Inhibition of Kv1.3 depolarizes microglia and reduces calcium entry mediated by P2X4 receptors by dissipating the electrochemical driving force for calcium.

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Section: P2x4 Expression Changes In Ischemic Stroke In Micementioning

confidence: 99%

Biophysical basis for Kv1.3 regulation of membrane potential changes induced by P2X4‐mediated calcium entry in microglia

Nguyen

Lucente

Chen

et al. 2020

Glia

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“…In particular, K Ca 3.1 blockade or downregulation in Skov-3 human ovarian cancer cells prevented ATP-induced cell migration possibly due to a loss of interaction between K Ca 3.1 and the purinergic receptor P2Y 2 [117]. Charybdotoxin impaired K Ca 3.1-mediated locomotion of human A7 and SKMEL28 melanoma cells and it decreased [Ca 2+ ] i and in consequence the polymerization reaction of F-actin [118].…”

Section: Tumor Cell-specific Functions Of Kca31mentioning

confidence: 99%

Cancer-Associated Intermediate Conductance Ca2+-Activated K+ Channel KCa3.1

Mohr

Steudel

Gross

et al. 2019

Cancers

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Several tumor entities have been reported to overexpress KCa3.1 potassium channels due to epigenetic, transcriptional, or post-translational modifications. By modulating membrane potential, cell volume, or Ca2+ signaling, KCa3.1 has been proposed to exert pivotal oncogenic functions in tumorigenesis, malignant progression, metastasis, and therapy resistance. Moreover, KCa3.1 is expressed by tumor-promoting stroma cells such as fibroblasts and the tumor vasculature suggesting a role of KCa3.1 in the adaptation of the tumor microenvironment. Combined, this features KCa3.1 as a candidate target for innovative anti-cancer therapy. However, immune cells also express KCa3.1 thereby contributing to T cell activation. Thus, any strategy targeting KCa3.1 in anti-cancer therapy may also modulate anti-tumor immune activity and/or immunosuppression. The present review article highlights the potential of KCa3.1 as an anti-tumor target providing an overview of the current knowledge on its function in tumor pathogenesis with emphasis on vasculo- and angiogenesis as well as anti-cancer immune responses.

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“…Blockage of the KCa3.1 or its down-regulation in SKOV-3 human OC cells prevented OC migration as a consequence of a loss of interaction between KCa3.1 and the purinergic receptor P2Y2 [123].…”

Section: Potassium Channelsmentioning

confidence: 95%

“…Recent studies revealed an involvement of KCa2.3 (KCNN3 gene) and KCa3.1 (KCNN4 gene) in OC pathogenesis [122,123]. KCNN3 mRNA expression was significantly lower in OC tissues compared with normal controls, suggesting its negative contribution in OC progression [122].…”

Section: Potassium Channelsmentioning

confidence: 99%

Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Altamura

Greco

Carratù

et al. 2021

Cancers

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Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

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Kca3.1 Activation Via P2y2 Purinergic Receptors Promotes Human Ovarian Cancer Cell (Skov-3) Migration

Cited by 18 publications

References 44 publications

Biophysical basis for Kv1.3 regulation of membrane potential changes induced by P2X4‐mediated calcium entry in microglia

Biophysical basis for Kv1.3 regulation of membrane potential changes induced by P2X4‐mediated calcium entry in microglia

Cancer-Associated Intermediate Conductance Ca2+-Activated K+ Channel KCa3.1

Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

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