Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein
| Autor: | Johann Kiehn, Gunnar Wendt-Nordahl, Wei Zhang, Kezhong Wu, Hugo A. Katus, Christoph A. Karle, Sven Kathöfer, Anna-Britt Wimmer, Bernd Gut, Dierk Thomas, Volker A. W. Kreye, Wolfgang Schoels |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
ERG1 Potassium Channel
congenital hereditary and neonatal diseases and abnormalities Patch-Clamp Techniques Potassium Channels Physiology hERG Xenopus laevis Transcriptional Regulator ERG Physiology (medical) Phorbol Esters Animals Humans cardiovascular diseases Phosphorylation Protein kinase A Cation Transport Proteins Protein Kinase C Protein kinase C biology Voltage-gated ion channel Chemistry Arrhythmias Cardiac Cyclic AMP-Dependent Protein Kinases Ether-A-Go-Go Potassium Channels Potassium channel Cell biology DNA-Binding Proteins Enzyme Activation Biochemistry Potassium Channels Voltage-Gated Mutagenesis Site-Directed Oocytes Trans-Activators biology.protein Tetradecanoylphorbol Acetate CAMP binding Female Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction |
| Zdroj: | Cardiovascular Research. 59:14-26 |
| ISSN: | 0008-6363 |
| Popis: | Objective: Patients with HERG-associated long QT syndrome typically develop tachyarrhythmias during physical or emotional stress. Previous studies have revealed that activation of the beta-adrenergic system and consecutive elevation of the intracellular cAMP concentration regulate HERG channels via protein kinase A-mediated phosphorylation of the channel protein and via direct interaction with the cAMP binding site of HERG. In contrast, the influence of the alpha-adrenergic signal transduction cascade on HERG currents as suggested by recent reports is less well understood. The aim of the present study was to elucidate the biochemical pathways of the protein kinase C (PKC)-dependent regulation of HERG currents. Methods: HERG channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. Results: Application of the phorbol ester PMA, an unspecific protein kinase activator, shifted the voltage dependence of HERG activation towards more positive potentials. This effect could be mimicked by activation of conventional PKC isoforms with thymeleatoxin. Coexpression of HERG with the beta-subunits minK or hMiRP1 did not alter the effect of PMA. Specific inhibition of PKC abolished the PMA-induced activation shift, suggesting that PKC is required within the regulatory mechanism. The PMA-induced effect could still be observed when the PKC-dependent phosphorylation sites in HERG were deleted by mutagenesis. Cytoskeletal proteins such as actin filaments or microtubules did not affect the HERG activation shift. Conclusion: In addition to the known effects of PKA and cAMP, HERG channels are also modulated by PKC. The molecular mechanisms of this PKC-dependent process are not completely understood but do not depend on direct PKC-dependent phosphorylation of the channel. |
| Databáze: | OpenAIRE |
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