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J Physiol Volume 571, Number 2, 349-359, March 1, 2006 DOI: 10.1113/jphysiol.2005.096818
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Molecular And Genomic

Ca2+-activated K+ channels in human melanoma cells are up-regulated by hypoxia involving hypoxia-inducible factor-1{alpha} and the von Hippel-Lindau protein

Nobuyoshi Tajima1, Kristina Schönherr1, Susanna Niedling1, Martin Kaatz2, Hiroshi Kanno3, Roland Schönherr1 and Stefan H. Heinemann1

1 Institute of Molecular Cell Biology, Research Unit Molecular and Cellular Biophysics, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747 Jena, Germany
2 Clinics for Dermatology, Friedrich Schiller University Jena, Erfurter Str. 35, D-07740 Jena, Germany
3 Department of Neurosurgery, Yokohama City, University Graduate School of Medicine, Yokohama 236-0004, Japan

Under chronic hypoxia, tumour cells undergo adaptive changes involving hypoxia-inducible factors (HIFs). Here we report that ion currents mediated by Ca2+-activated K+ (KCa) channels in human melanoma IGR1 cells are increased by chronic hypoxia (3% O2), as well as by hypoxia mimetics. This increase involves the HIF system as confirmed by overexpression of HIF-1{alpha} or the von Hippel-Lindau tumour suppressor gene. Under normoxic conditions the KCa channels in IGR1 cells showed pharmacological characteristics of intermediate conductance KCa subtype IK channels, whereas the subtype SK2 channels were up-regulated under hypoxia, shown with pharmacological tools and with mRNA analysis. Hypoxia increased cell proliferation, but the KCa channel blockers apamin and charybdotoxin slowed down cell growth, particularly under hypoxic conditions. Similar results were obtained for the cell line IGR39 and for acutely isolated cells from a biopsy of a melanoma metastasis. Thus, up-regulation of KCa channels may be a novel mechanism by which HIFs can contribute to the malignant phenotype of human tumour cells.

(Received 17 August 2005; accepted after revision 3 January 2006; first published online 5 January 2006)
Corresponding author S. H. Heinemann: Institute of Molecular Cell Biology, Research Unit Molecular and Cellular Biophysics, Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747 Jena, Germany. Email: stefan.h.heinemann{at}uni-jena.de




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