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(Circulation. 2002;106:1493.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Human Cardiac Inwardly-Rectifying K⁺ Channel Kir_2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System

Christoph A. Karle, MD; Edgar Zitron, BSc; Wei Zhang, MD; Gunnar Wendt-Nordahl, BSc; Sven Kathöfer, MD; Dierk Thomas, MD; Bernd Gut, BSc; Eberhard Scholz, BSc; Christian-Friedrich Vahl, MD; Hugo A. Katus, MD; Johann Kiehn, MD

From the Department of Cardiology (C.A.K., E.Z., W.Z., G.W.-N., S.K., D.T., B.G., E.S., H.A.K., J.K.) and the Department of Cardiac Surgery (C.-F.V.), University of Heidelberg Medical School, Heidelberg, Germany.

Correspondence to Johann Kiehn, MD, Department of Cardiology, University of Heidelberg Medical School, Bergheimerstraße 58, D-69115 Heidelberg, Germany. E-mail johann_kiehn{at}med.uni-heidelberg.de

Background— Protein kinases A (PKA) and C (PKC) are activated in ischemic preconditioning and heart failure, conditions in which patients develop arrhythmias. The native inward rectifier potassium current (IK₁) plays a central role in the stabilization of the resting membrane potential and the process of arrhythmogenesis. This study investigates the functional relationship between PKC and IK₁.

Methods and Results— In whole-cell patch-clamp experiments with isolated human atrial cardiomyocytes, the IK₁ was reduced by 41% when the nonspecific activator of PKC phorbol 12 myristate 13-acetate (PMA; 100 nmol/L) was applied. To investigate the effects of PKC on cloned channel underlying parts of the native IK₁, we expressed Kir_2.1b heterologously in Xenopus oocytes and measured currents with the double-electrode voltage-clamp technique. PMA decreased the current by an average of 68%, with an IC₅₀ of 0.68 nmol/L. The inactive compound 4--PMA was ineffective. Thymeleatoxin and 1-oleolyl-2-acetyl-sn-glycerol, 2 specific activators of PKC, produced effects similar to those of PMA. Inhibitors of PKC, ie, staurosporine and chelerytrine, could inhibit the PMA effect (1 nmol/L) significantly. After mutation of the PKC phosphorylation sites (especially S64A and T353A), PMA became ineffective.

Conclusions— The human IK₁ in atrial cardiomyocytes and one of its underlying ion channels, the Kir_2.1b channel, is inhibited by PKC-dependent signal transduction pathways, possibly contributing to arrhythmogenesis in patients with structural heart disease in which PKC is activated.

Key Words: ion channels • signal transduction • arrhythmia • electrophysiology

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