This Article Full Text Full Text (PDF) All Versions of this Article: 106/12/1493    most recent 01.CIR.0000029747.53262.5Cv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Karle, C. A. Articles by Kiehn, J. Search for Related Content PubMed PubMed Citation Articles by Karle, C. A. Articles by Kiehn, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB 12-O-TETRADECANOYLPHORBOL-13-ACETATE Related Collections Arrhythmias, clinical electrophysiology, drugs

(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

This article has been cited by other articles:

				W. Zhang, E. Zitron, M. Homme, L. Kihm, C. Morath, D. Scherer, S. Hegge, D. Thomas, C. P. Schmitt, M. Zeier, et al. Aquaporin-1 Channel Function Is Positively Regulated by Protein Kinase C J. Biol. Chem., July 20, 2007; 282(29): 20933 - 20940. [Abstract] [Full Text] [PDF]

				N. Voigt, A. Friedrich, M. Bock, E. Wettwer, T. Christ, M. Knaut, R. H. Strasser, U. Ravens, and D. Dobrev Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation Cardiovasc Res, June 1, 2007; 74(3): 426 - 437. [Abstract] [Full Text] [PDF]

				D. Dobrev, A. Friedrich, N. Voigt, N. Jost, E. Wettwer, T. Christ, M. Knaut, and U. Ravens The G Protein-Gated Potassium Current IK,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation Circulation, December 13, 2005; 112(24): 3697 - 3706. [Abstract] [Full Text] [PDF]

				J. Fauconnier, A. Lacampagne, J.-M. Rauzier, G. Vassort, and S. Richard Ca2+-dependent reduction of IK1 in rat ventricular cells: A novel paradigm for arrhythmia in heart failure? Cardiovasc Res, November 1, 2005; 68(2): 204 - 212. [Abstract] [Full Text] [PDF]

				Y. Fang, G. Schram, V. G. Romanenko, C. Shi, L. Conti, C. A. Vandenberg, P. F. Davies, S. Nattel, and I. Levitan Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2 Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1134 - C1144. [Abstract] [Full Text] [PDF]

				X. Du, H. Zhang, C. Lopes, T. Mirshahi, T. Rohacs, and D. E. Logothetis Characteristic Interactions with Phosphatidylinositol 4,5-Bisphosphate Determine Regulation of Kir Channels by Diverse Modulators J. Biol. Chem., September 3, 2004; 279(36): 37271 - 37281. [Abstract] [Full Text] [PDF]

				E. Zitron, C. Kiesecker, S. Luck, S. Kathofer, D. Thomas, V. A.W Kreye, J. Kiehn, H. A Katus, W. Schoels, and C. A Karle Human cardiac inwardly rectifying current IKir2.2 is upregulated by activation of protein kinase A Cardiovasc Res, August 15, 2004; 63(3): 520 - 527. [Abstract] [Full Text] [PDF]

				J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon Pharmacology of cardiac potassium channels Cardiovasc Res, April 1, 2004; 62(1): 9 - 33. [Abstract] [Full Text] [PDF]

				D. Thomas, W. Zhang, K. Wu, A.-B. Wimmer, B. Gut, G. Wendt-Nordahl, S. Kathofer, V. A.W. Kreye, H. A. Katus, W. Schoels, et al. Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein Cardiovasc Res, July 1, 2003; 59(1): 14 - 26. [Abstract] [Full Text] [PDF]

				W.-Z. Zeng, X.-J. Li, D. W. Hilgemann, and C.-L. Huang Protein Kinase C Inhibits ROMK1 Channel Activity via a Phosphatidylinositol 4,5-Bisphosphate-dependent Mechanism J. Biol. Chem., May 2, 2003; 278(19): 16852 - 16856. [Abstract] [Full Text] [PDF]