Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas

Preußat, Katja; Beetz, Christian; Schrey, M.P.; Kraft, Robert A.; Wölfl, Stefan; Kalff, Rolf; Patt, Stephan

doi:10.1016/s0304-3940(03)00562-7

Cited by 92 publications

(75 citation statements)

References 14 publications

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“…Expression of Kv1.3 and Kv1.5 mRNAs was detected by RT-PCR in human astrocytoma specimens. An inverse correlation has been observed between the level of Kv1.5 and the grade of tumor malignancy, whereas no such correlation is evident for Kv1.3 expression [14].…”

Section: Introductionmentioning

confidence: 88%

The Kv1.3 potassium channel is localized to the cis‐Golgi and Kv1.6 is localized to the endoplasmic reticulum in rat astrocytes

2014

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The functions of voltage‐gated potassium (Kv) channels in neurons have been well defined, whereas their roles in glial cells are not fully understood. Kv1.1, Kv1.3 and Kv1.6 are endogenously expressed in C6 astrocytoma cells, but their trafficking and subcellular localization have not been well studied. In C6 cells, Kv1.1 was localized to the cell surface, Kv1.3 was predominantly localized in the cis‐Golgi, and Kv1.6 was enriched in the endoplasmic reticulum. Disruption of the Golgi stacks with brefeldin A treatment redirected Kv1.3 to the endoplasmic reticulum, further confirming that Kv1.3 was localized in the Golgi. Denaturing and reducing immunoblot analysis identified an expected Kv1.3 monomer and an unexpected Kv1.3 dimer/aggregate. These two forms had different protein half‐lives: that of the monomer form T1/2 was 5.1 h, whereas the dimer/aggregate form was stable over the 8‐h measurement period. The Kv1.3 dimer/aggregate form on immunoblots appeared to be correlated with its Golgi retention, based on examination with several cell types that expressed Kv1.3. Glycosidase treatment showed that Kv1.3 contained complex‐type N‐glycans terminated with sialic acids, suggesting that Kv1.3 had traveled to the trans‐Golgi network for sialylation before it was recycled to the cis‐Golgi for retention. Inhibition of N‐glycosylation did not affect Kv1.3 localization, indicating that N‐glycans did not play a role in its Golgi retention. Thus, Kv1.3 appears to be distributed to the cis‐Golgi membrane of rat astrocytes in a similar way as a Golgi resident protein, and this unusual distribution appears to be correlated with its SDS/2‐mercaptoethanol‐resistant dimer/aggregate forms on immunoblots.

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Section: Introductionmentioning

confidence: 88%

The Kv1.3 potassium channel is localized to the cis‐Golgi and Kv1.6 is localized to the endoplasmic reticulum in rat astrocytes

2014

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“…Although it has been proposed for many years that K 1 conduction is important for changes in membrane potential during cell-cycle progression, or for regulation of cell volume in proliferating cells, it is clear that not all members of the K 1 channel superfamily can support these roles. Only a select group of K 1 channels [K v 1.3, K 2P 9.1, human ether-à-go-go (hEAG1), hEAG2, hERG1)] influence proliferation and have been linked to cancer (Bianchi et al, 1998;Pardo et al, 1999;Fraser et al, 2003;Pei et al, 2003;Preussat et al, 2003;Tajima et al, 2006;Huang et al, 2012), suggesting that channel properties other than K 1 selectivity are important. Intriguingly, of this small group, hERG1, hEAG1, and hEAG2 belong to the same subfamily and are closely related.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Channel Block Is Required to Inhibit Cellular Transformation by Human Ether-à-Go-Go–Related Gene (hERG1) Potassium Channels

et al. 2014

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Both human ether-à-go-go-related gene (hERG1) and the closely related human ether-à-go-go (hEAG1) channel are aberrantly expressed in a large proportion of human cancers. In the present study, we demonstrate that transfection of hERG1 into mouse fibroblasts is sufficient to induce many features characteristic of malignant transformation. An important finding of this work is that this transformation could be reversed by chronic incubation (for 2-3 weeks) with the hERG channel blocker dofetilide (100 nM), whereas more acute applications (for 1-2 days) were ineffective. The hERG1 expression resulted in a profound loss of cell contact inhibition, multiple layers of overgrowing cells, and high saturation densities. Cells also changed from fibroblast-like to a more spindle-shaped morphology, which was associated with a smaller cell size, a dramatic increase in cell polarization, a reduction in the number of actin stress fibers, and less punctate labeling of focal adhesions. Analysis of single-cell migration and scratch-wound closure clearly demonstrated that hERG1-expressing cells migrated more rapidly than vector-transfected control cells. In contrast to previous studies on hEAG1, there were no increases in rates of proliferation, or loss of growth factor dependency; however, hERG1-expressing cells were capable of substrateindependent growth. Allogeneic transplantation of hERG1-expressing cells into nude mice resulted in an increased incidence of tumors. In contrast to hEAG1, the mechanism of cellular transformation is dependent on ion conduction. Trafficking-deficient and conduction-deficient hERG1 mutants also prevented cellular transformation. These results provide evidence that hERG1 expression is sufficient to induce cellular transformation by a mechanism distinct from hEAG1. The most important conclusion of this study is that selective hERG1 channel blockers have therapeutic potential in the treatment of hERG1-expressing cancers.

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“…A K V channel attracting particular attention has been K V 1.5, which switches on in response to depolarization past about Ϫ40 mV, has moderate-to-slow inactivation, and is regulated by factors, including acid and hydrogen peroxide (9,48). K V 1.5 is perhaps best known in relation to vascular smooth muscle and cardiac muscle (32,33,36,37,42), but it also occurs in GH 3 pituitary cells, tumors, oligodendrocyte precursor cells, macrophages, and somato dendritic Purkinje cells of the cerebellum (12,14,38,41,52).…”

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confidence: 99%

K_v1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress

Fountain

Cheong²,

Li³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas

Cited by 92 publications

References 14 publications

The Kv1.3 potassium channel is localized to the cis‐Golgi and Kv1.6 is localized to the endoplasmic reticulum in rat astrocytes

The Kv1.3 potassium channel is localized to the cis‐Golgi and Kv1.6 is localized to the endoplasmic reticulum in rat astrocytes

Long-Term Channel Block Is Required to Inhibit Cellular Transformation by Human Ether-à-Go-Go–Related Gene (hERG1) Potassium Channels

K_v1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress

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Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas

Cited by 92 publications

References 14 publications

The Kv1.3 potassium channel is localized to the cis‐Golgi and Kv1.6 is localized to the endoplasmic reticulum in rat astrocytes

The Kv1.3 potassium channel is localized to the cis‐Golgi and Kv1.6 is localized to the endoplasmic reticulum in rat astrocytes

Long-Term Channel Block Is Required to Inhibit Cellular Transformation by Human Ether-à-Go-Go–Related Gene (hERG1) Potassium Channels

Kv1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress

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K_v1.5 potassium channel gene regulation by Sp1 transcription factor and oxidative stress