title: Alternatively Spliced Isoforms of KV10.1 Potassium Channels Modulate Channel Properties and Can Activate Cyclin-dependent Kinase in Xenopus Oocytes.
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.
authors.affiliation: From the Department of Molecular Biology of Neuronal Signals and.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ramos Gomes
authors.affiliation: the Oncophysiology Group, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Romaniello
authors.affiliation: the Oncophysiology Group, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany.
authors.forename: Araceli
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: From the Department of Molecular Biology of Neuronal Signals and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Weber
authors.affiliation: From the Department of Molecular Biology of Neuronal Signals and.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Narayanan
authors.affiliation: From the Department of Molecular Biology of Neuronal Signals and.
authors.forename: Maryna
authors.initials: M
authors.lastname: Psol
authors.affiliation: the Oncophysiology Group, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075 Göttingen, Germany pardo@em.mpg.de.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Pardo
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D020033:Protein Isoforms; D018844:Cyclin-Dependent Kinases
keywords: KCNH1; KV10.1; RNA splicing; cell cycle; glycosylation; post-transcriptional regulation; potassium channel