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First published online 1 November 2005
doi: 10.1242/jcs.02635

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Downregulation of the HERG (KCNH2) K⁺ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation

Hugh Chapman^1,*, Cia Ramström^1,2,*, Laura Korhonen³, Mika Laine^1,4, Kenneth T. Wann⁵, Dan Lindholm^1,3, Michael Pasternack¹ and Kid Törnquist^1,2,

¹ Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Haartmaninkatu 8, FI-00290, Helsinki, Finland
² Department of Biology, Åbo Akademi University, Artillerigatan 6, FI-20520 Turku, Finland
³ Department of Neuroscience, Unit of Neurobiology, Uppsala University, BMC, Box 587, SE-75123 Uppsala, Sweden
⁴ Department of Cardiology, Helsinki University Central Hospital, Stenbäckinkatu 9, FI-00290 Helsinki, Finland
⁵ Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF1 3XF, UK

Author for correspondence (e-mail: kid.tornqvist{at}abo.fi)

Accepted 4 August 2005

The HERG (KCNH2) potassium channel underlies the rapid component of the delayed rectifier current (I_kr), a current contributing to the repolarisation of the cardiac action potential. Mutations in HERG can cause the hereditary forms of the short-QT and long-QT syndromes, predisposing to ventricular arrhythmias and sudden cardiac death. HERG is expressed mainly in the cell membrane of cardiac myocytes, but has also been identified in cell membranes of a range of other cells, including smooth muscle and neurones. The mechanisms regulating the surface expression have however not yet been elucidated. Here we show, using stable HERG-expressing HEK 293 cells, that ceramide evokes a time-dependent decrease in HERG current which was not attributable to a change in gating properties of the channel. Surface expression of the HERG channel protein was reduced by ceramide as shown by biotinylation of surface proteins, western blotting and immunocytochemistry. The rapid decline in HERG protein after ceramide stimulation was due to protein ubiquitylation and its association with lysosomes. The results demonstrate that the surface expression of HERG is strictly regulated, and that ceramide modifies HERG currents and targets the protein for lysosomal degradation.

Key words: Sphingolipids, Channels, Internalisation, Ubiquitin, HERG, Ceramide

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