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Science 295 (5554): 496-499

Copyright © 2002 by the American Association for the Advancement of Science

Requirement of a Macromolecular Signaling Complex for beta  Adrenergic Receptor Modulation of the KCNQ1-KCNE1 Potassium Channel

Steven O. Marx,* Junko Kurokawa,* Steven Reiken, Howard Motoike, Jeanine D'Armiento, Andrew R. Marks, Robert S. Kassdagger

Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by beta  adrenergic receptor (beta AR) activation, which increases the slow outward potassium ion current (IKS). Mutations in two human IKS channel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that beta AR modulation of IKS requires targeting of adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) and protein phosphatase 1 (PP1) to hKCNQ1 through the targeting protein yotiao. Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D). Identification of the hKCNQ1 macromolecular complex provides a mechanism for SNS modulation of cardiac APD through IKS.

Department of Pharmacology, Center for Molecular Cardiology, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
*   These authors contributed equally to this report.

dagger    To whom correspondence should be addressed. E-mail: rsk20{at}columbia.edu

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{beta}-Adrenergic regulation requires direct anchoring of PKA to cardiac CaV1.2 channels via a leucine zipper interaction with A kinase-anchoring protein 15.
J. T. Hulme, T. W.-C. Lin, R. E. Westenbroek, T. Scheuer, and W. A. Catterall (2003)
PNAS 100, 13093-13098
   Abstract »    Full Text »    PDF »
Physiological Genomics of Human Arteries: Quantitative Relationship Between Gene Expression and Arterial Stiffness.
S. Durier, C. Fassot, S. Laurent, P. Boutouyrie, J.-P. Couetil, E. Fine, P. Lacolley, V. J. Dzau, and R. E. Pratt (2003)
Circulation 108, 1845-1851
   Abstract »    Full Text »    PDF »
Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes.
M. Stengl, P. G A Volders, M. B Thomsen, R. L H M G Spatjens, K. R Sipido, and M. A Vos (2003)
J. Physiol. 551, 777-786
   Abstract »    Full Text »    PDF »
Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family.
L. Ma, C. Lin, S. Teng, Y. Chai, R. Bahring, V. Vardanyan, L. Li, O. Pongs, and R. Hui (2003)
Cardiovasc Res 59, 612-619
   Abstract »    Full Text »    PDF »
Sodium/Calcium Exchanger (NCX1) Macromolecular Complex.
D. H. Schulze, M. Muqhal, W. J. Lederer, and A. M. Ruknudin (2003)
J. Biol. Chem. 278, 28849-28855
   Abstract »    Full Text »    PDF »
Phosphorylation of the IKs Channel Complex Inhibits Drug Block: Novel Mechanism Underlying Variable Antiarrhythmic Drug Actions.
T. Yang, H. Kanki, and D. M. Roden (2003)
Circulation 108, 132-134
   Abstract »    Full Text »    PDF »
Stimulation of Protein Kinase C Inhibits Bursting in Disease-Linked Mutant Human Cardiac Sodium Channels.
M. Tateyama, J. Kurokawa, C. Terrenoire, I. Rivolta, and R.S. Kass (2003)
Circulation 107, 3216-3222
   Abstract »    Full Text »    PDF »
Long QT syndrome and anaesthesia.
P. D. Booker, S. D. Whyte, and E. J. Ladusans (2003)
Br. J. Anaesth. 90, 349-366
   Abstract »    Full Text »    PDF »
Leucine Zipper Domain Targets cAMP-dependent Protein Kinase to Mammalian BK Channels.
L. Tian, L. S. Coghill, S. H.-F. MacDonald, D. L. Armstrong, and M. J. Shipston (2003)
J. Biol. Chem. 278, 8669-8677
   Abstract »    Full Text »    PDF »
Protein kinase A-anchoring (AKAP) domains in brefeldin A-inhibited guanine nucleotide-exchange protein 2 (BIG2).
H. Li, R. Adamik, G. Pacheco-Rodriguez, J. Moss, and M. Vaughan (2003)
PNAS 100, 1627-1632
   Abstract »    Full Text »    PDF »
Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel.
J. Kurokawa, L. Chen, and R. S. Kass (2003)
PNAS 100, 2122-2127
   Abstract »    Full Text »    PDF »

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