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PMID: 11799244 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.

Science (New York, N.Y.) ·Vol. 295 ·No. 5554 ·2002-01-18 ·Pages 496-9

Marx SO, Kurokawa J, Reiken S, Motoike H, D'Armiento J, Marks AR, Kass RS

Abstract

Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by beta adrenergic receptor (betaAR) activation, which increases the slow outward potassium ion current (IKS). Mutations in two human I(KS) channel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that betaAR modulation of I(KS) 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.

MeSH Terms

8-Bromo Cyclic Adenosine Monophosphate/pharmacology A Kinase Anchor Proteins Action Potentials Adaptor Proteins, Signal Transducing Amino Acid Substitution Animals CHO Cells Carrier Proteins/metabolism Cricetinae Cyclic AMP/metabolism Cyclic AMP-Dependent Protein Kinases/metabolism Cytoskeletal Proteins/metabolism Humans KCNQ Potassium Channels KCNQ1 Potassium Channel Leucine Zippers Macromolecular Substances Mice Mice, Transgenic Mutation Myocardium/cytology,metabolism Phosphoprotein Phosphatases/metabolism Phosphorylation Potassium/metabolism Potassium Channels/chemistry,genetics,metabolism Potassium Channels, Voltage-Gated Protein Phosphatase 1 Receptors, Adrenergic, beta/metabolism Recombinant Fusion Proteins/chemistry,metabolism Signal Transduction

Chemicals

A Kinase Anchor Proteins AKAP9 protein, human Adaptor Proteins, Signal Transducing Carrier Proteins Cytoskeletal Proteins KCNQ Potassium Channels KCNQ1 Potassium Channel KCNQ1 protein, human Kcnq1 protein, mouse Macromolecular Substances Potassium Channels Potassium Channels, Voltage-Gated Receptors, Adrenergic, beta Recombinant Fusion Proteins potassium channel protein I(sk) 8-Bromo Cyclic Adenosine Monophosphate Cyclic AMP Cyclic AMP-Dependent Protein Kinases Phosphoprotein Phosphatases Protein Phosphatase 1 Potassium

Authors & Affiliations

7 authors, click to expand affiliations / ORCID

Marx Steven O

Department of Pharmacology, Center for Molecular Cardiology, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

Kurokawa Junko

Reiken Steven

Motoike Howard

D'Armiento Jeanine

Marks Andrew R

Kass Robert S

Article Info

Journal

Science (New York, N.Y.)

Abbr.

Science

ISSN

1095-9203

DOI

10.1126/science.1066843

Published

2002-01-18

Pages

496-9

Language

English

Region

United States

NLM ID

0404511

Subset

Grants

NHLBI NIH HHS · P01HL67849-01 · United States

NIAID NIH HHS · R01-AI39794 · United States

NHLBI NIH HHS · R01-HL44365-07 · United States

NHLBI NIH HHS · R01-HL56180 · United States

NHLBI NIH HHS · R01-HL56810-05 · United States

NHLBI NIH HHS · R01-HL61503 · United States

NHLBI NIH HHS · R01-HL68093 · United States

External Links

PubMed source DOI: 10.1126/science.1066843 View journal details

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Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.

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