Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy

Ge, Lisheng; Hoa, Neil; Wilson, Zechariah; Arismendi-Morillo, Gabriel; Kong, Xianguo; Tajhya, Rajeev B.; Beeton, Christine; Jadus, Martin R.

doi:10.1016/j.intimp.2014.06.040

Cited by 78 publications

(82 citation statements)

References 207 publications

(196 reference statements)

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“…47, 48, 49 KCa1.1 α contains multiple alternating splicing sites with more than 30 splice variants identified in different tissues and species. 16, 50, 51 Alternative splicing of KCa1.1 α can affect not only the potassium-conducting properties of the channel but also its interactions with signaling molecules and its subcellular localization. Immunocytochemistry on skeletal myoblasts showed a loss of plasma membrane expression of KCa1.1 α in DM1 cells, but these cells retained its nuclear expression.…”

Section: Discussionmentioning

confidence: 99%

Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts

Tajhya

Tanner

et al. 2016

Cell Death Dis

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Myoblasts are mononucleated precursors of myofibers; they persist in mature skeletal muscles for growth and regeneration post injury. During myotonic dystrophy type 1 (DM1), a complex autosomal-dominant neuromuscular disease, the differentiation of skeletal myoblasts into functional myotubes is impaired, resulting in muscle wasting and weakness. The mechanisms leading to this altered differentiation are not fully understood. Here, we demonstrate that the calcium- and voltage-dependent potassium channel, KCa1.1 (BK, Slo1, KCNMA1), regulates myoblast proliferation, migration, and fusion. We also show a loss of plasma membrane expression of the pore-forming α subunit of KCa1.1 in DM1 myoblasts. Inhibiting the function of KCa1.1 in healthy myoblasts induced an increase in cytosolic calcium levels and altered nuclear factor kappa B (NFκB) levels without affecting cell survival. In these normal cells, KCa1.1 block resulted in enhanced proliferation and decreased matrix metalloproteinase secretion, migration, and myotube fusion, phenotypes all observed in DM1 myoblasts and associated with disease pathogenesis. In contrast, introducing functional KCa1.1 α-subunits into DM1 myoblasts normalized their proliferation and rescued expression of the late myogenic marker Mef2. Our results identify KCa1.1 channels as crucial regulators of skeletal myogenesis and suggest these channels as novel therapeutic targets in DM1.

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Section: Discussionmentioning

confidence: 99%

Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts

Tajhya

Tanner

et al. 2016

Cell Death Dis

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“…Among the large family of potassium channels, BKCa is also involved in promoting cancer cell proliferation, migration and invasion [4, 6]. Abdallah Mound et al recently found that ATP induced cell proliferation could be effectively blocked in MCF-7 cells by downregulation of BKCa [10].…”

Section: Discussionmentioning

confidence: 99%

“…It modulates vasomotor and nerve excitability by regulating membrane potential and calcium signaling [4, 5]. Recent studies report that BKCa is aberrantly expressed in many neoplastic cells and participate in cell growth and metastasis [1, 6]. Specifically, the BKCa coding gene (KCNMA1) is amplified in nearly 1.9% of breast cancers.…”

Section: Introductionmentioning

confidence: 99%

BKCa promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK

Zheng

et al. 2016

Oncotarget

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BKCa is a large conductance calcium activated potassium channel promoting prostate cancer cell proliferation, although the mechanism is not fully elucidated. In addition, whether BKCa is involved in metastasis of prostate cancer remains to be explored. Here, we report that BKCa is overexpressed in prostate cancer. BKCa expression positively correlates with Ki67 index and gleason score of prostate cancer. Upregulation of BKCa promoted proliferation, migration and invasion of prostate cancer cells. On the contrary, downregulation of BKCa inhibited growth and metastasis of prostate cancer cells both in vitro and in vivo. Moreover, the ion-conducting function of BKCa contributed moderately to prostate cancer proliferation and migration, although, this was not the primary mechanism. BKCa action was mainly mediated through forming a functional complex with αvβ3 integrin. The BKCa/αvβ3 integrin complex promoted FAK phosphorylation independent of the channel activity. Overexpression of BKCa enhanced its association with αvβ3 integrin and FAK which increased FAK phosphorylation. Conversely, disrupting the complex by downregulation of BKCa reduced FAK phosphorylation. Finally, blocking of αvβ3 integrin or p-FAK activity using LM609 or Y15 markedly abrogated BKCa-enhanced cell proliferation and migration. Taken together, these results suggest that targeting BKCa/αvβ3/FAK may inaugurate innovative approaches to inhibit prostate cancer growth and metastasis.

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“…SAK CA , BK Ca Alpha, SLO1, MaxiK). 149 They are present in a number of cell and tissue types, including vascular smooth muscle, atrium and ventricles. 150 BK channels are found not only in the sarcolemma, but also in membranes of the endoplasmic reticulum, the Golgi apparatus, and mitochondria.…”

Section: Cardiac Sac: Molecular Candidatesmentioning

confidence: 99%

“…150 BK channels are found not only in the sarcolemma, but also in membranes of the endoplasmic reticulum, the Golgi apparatus, and mitochondria. 149 …”

Section: Cardiac Sac: Molecular Candidatesmentioning

confidence: 99%

Cardiac Mechano-Gated Ion Channels and Arrhythmias

Peyronnet

Nerbonne

Kohl

2016

Circulation Research

175

167

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Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, are exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intra-cardially, and are thus maintained even in heart transplant recipients. Although mechano-sensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechano-transduction have started to emerge. Mechano-gated ion channels are cardiac mechano-receptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them. Cardiac electrophysiology is acutely affected by the heart’s mechanical environment. Mechano-electric feedback affects excitability, conduction, and electrical load, and remains an underestimated player in arrhythmogenesis. The utility of therapeutic interventions targeting acute mechano-electrical transduction is an open field worthy of further study.

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Big Potassium (BK) ion channels in biology, disease and possible targets for cancer immunotherapy

Cited by 78 publications

References 207 publications

Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts

Functional KCa1.1 channels are crucial for regulating the proliferation, migration and differentiation of human primary skeletal myoblasts

BKCa promotes growth and metastasis of prostate cancer through facilitating the coupling between αvβ3 integrin and FAK

Cardiac Mechano-Gated Ion Channels and Arrhythmias

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