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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}

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S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh (2007)
Physiol Rev 87, 425-456
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IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits.
F. Suto, W. Zhu, A. Chan, and G. J. Gross (2007)
Am J Physiol Heart Circ Physiol 292, H1782-H1788
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The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family.
T. Jespersen, M. Membrez, C. S. Nicolas, B. Pitard, O. Staub, S.-P. Olesen, I. Baro, and H. Abriel (2007)
Cardiovasc Res 74, 64-74
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Dopamine modulation of neuronal Na+ channels requires binding of A kinase-anchoring protein 15and PKA by a modified leucine zipper motif.
W. P. Few, T. Scheuer, and W. A. Catterall (2007)
PNAS 104, 5187-5192
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Regulation of Endocytic Recycling of KCNQ1/KCNE1 Potassium Channels.
G. Seebohm, N. Strutz-Seebohm, R. Birkin, G. Dell, C. Bucci, M. R. Spinosa, R. Baltaev, A. F. Mack, G. Korniychuk, A. Choudhury, et al. (2007)
Circ. Res. 100, 686-692
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Mouse models of long QT syndrome.
G. Salama and B. London (2007)
J. Physiol. 578, 43-53
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Action potential characterization in intact mouse heart: steady-state cycle length dependence and electrical restitution.
B. C. Knollmann, T. Schober, A. O. Petersen, S. G. Sirenko, and M. R. Franz (2007)
Am J Physiol Heart Circ Physiol 292, H614-H621
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