Downregulation of the HERG (KCNH2) K+ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation
| Autor: | Hugh Chapman, Mika Laine, Cia Ramström, Kid Törnquist, Michael Pasternack, Dan Lindholm, Kenneth Taylor Wann, Laura Korhonen |
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| Rok vydání: | 2005 |
| Předmět: |
ERG1 Potassium Channel
congenital hereditary and neonatal diseases and abnormalities Ceramide Time Factors hERG Down-Regulation Gene Expression Ceramides Membrane Potentials chemistry.chemical_compound Downregulation and upregulation Humans Myocyte cardiovascular diseases Cells Cultured biology Ubiquitin HEK 293 cells Cardiac action potential Cell Biology Sphingolipid Ether-A-Go-Go Potassium Channels Potassium channel Cell biology chemistry Biochemistry Potassium Channels Voltage-Gated biology.protein Lysosomes Ion Channel Gating Protein Processing Post-Translational |
| Zdroj: | Journal of Cell Science. 118:5325-5334 |
| ISSN: | 1477-9137 0021-9533 |
| Popis: | The HERG (KCNH2) potassium channel underlies the rapid component of the delayed rectifier current (Ikr), 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. |
| Databáze: | OpenAIRE |
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