Abstract
KV10.1 is a voltage-gated potassium channel expressed selectively in the mammalian brain but also aberrantly in cancer cells. In this study we identified short splice variants of KV10.1 resulting from exon-skipping events (E65 and E70) in human brain and cancer cell lines. The presence of the variants was confirmed by Northern blot and RNase protection assays. Both variants completely lacked the transmembrane domains of the channel and produced cytoplasmic proteins without channel function. In a reconstituted system, both variants co-precipitated with the full-length channel and induced a robust down-regulation of KV10.1 current when co-expressed with the full-length form, but their effect was mechanistically different. E65 required a tetramerization domain and induced a reduction in the overall expression of full-length KV10.1, whereas E70 mainly affected its glycosylation pattern. E65 triggered the activation of cyclin-dependent kinases in Xenopus laevis oocytes, suggesting a role in cell cycle control. Our observations highlight the relevance of noncanonical functions for the oncogenicity of KV10.1, which need to be considered when ion channels are targeted for cancer therapy.
Highlights
Contribution of KV10.1 to tumor progression does not fully rely on its primary function as an ion channel
KV10.1 Variants in Melanoma Cell Lines—Astemizole reduces the proliferation of many cancer cell lines, and its effect can be at least in part attributed to inhibition of the KV10.1 channel [7, 54]
A band of the expected size was detected in both cell lines, indicating that KV10.1 is expressed in both IPC298 and IGR39 cells (Fig. 1B)
Summary
Contribution of KV10.1 to tumor progression does not fully rely on its primary function as an ion channel. Two splice variants of the mammalian KV10.1 have been identified, termed KV10.1a and KV10.1b [4, 47, 48] Both form active ion channels with properties that are very similar to each other. A third splice variant cloned from Drosophila (Eag80) is composed of only the N and C termini of the channel. It does not produce an active ion channel, it activates a signaling cascade leading to altered cell architecture [49]. Alternative Splicing of KV10.1 ion channel splice variants is crucial to understanding the mechanisms underlying the progression and resistance of oncologic diseases
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