© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Human cardiac inwardly rectifying current IKir2.2 is upregulated by activation of protein kinase A
aDepartment of Cardiology, Medical University Hospital Heidelberg, Bergheimerstrasse 58, D-69115, Heidelberg, Germany
bDepartment of Physiology and Pathophysiology, Medical University Hospital Heidelberg, Germany
* Corresponding author. Tel.: +49-6221-5638630; fax: +49-6221-565515. Email address: christoph1_karle{at}med.uni-heidelberg.de
Objective: The cardiac inwardly rectifying potassium current IK1 and its molecular correlates Kir2.1 and Kir2.2 play an important role in cardiac repolarisation and in the pathogenesis of hereditary long-QT syndrome (LQTS-7). Protein kinases A (PKA) and C (PKC) are key enzymes in adrenergic signal transduction, inducing arrhythmias in heart disease. This study investigated the regulation of Kir2.2 (KCNJ12) by PKA. Methods: Cloned Kir2.2 channels were expressed heterologously in Xenopus oocytes and currents were measured with the double-electrode voltage–clamp technique. Results: After activation of PKA by forskolin (100 µmol/l) or Ro-20-1724 (100 µmol/l), wild type currents at –120 mV were increased by 93.7% and 79.0%, respectively. Coapplication of the PKA inhibitor KT-5720 (2.5 µmol/l) attenuated this effect. No significant changes were apparent after mutation of the single PKA consensus site S430. In addition, removal of all four PKC consensus sites in Kir2.2 induced a phorbolester-mediated current increase which could be suppressed by PKA inhibitors H-89 (50 µmol/l) and KT-5720 (2.5 µmol/l). Conclusions: This study demonstrates antagonistic effects of PKA and PKC in the regulation of Kir2.2. Phosphorylation by PKC has been shown to cause an inhibition of Kir2.2 currents, whereas activation of PKA leads to current upregulation.
KEYWORDS Arrhythmia (mechanisms); K-channel; Protein kinase A; Protein kinase C; Signal transduction
Time for primary review 24 days
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