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

• Published in: Science (American Association for the Advancement of Science) 2002-01, Vol.295 (5554), p.496-499
• Main Authors: Marx, Steven O., Kurokawa, Junko, Reiken, Steven, Motoike, Howard, D'Armiento, Jeanine, Marks, Andrew R., Kass, Robert S.
• Format: Article
• Language: English
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; A Kinase Anchor Proteins; Action Potentials; Adaptor Proteins, Signal Transducing; Amino Acid Substitution; Anatomy; Animals; Antibodies; b-Adrenergic receptors; Beta adrenoceptors; Calcium; Cardiology; Carrier Proteins - metabolism; Cell cycle; Centrosomes; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytoskeletal Proteins - metabolism; Eggs; Humans; Ions; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Leucine Zippers; Literary Devices; Macromolecular Substances; Mice; Mice, Transgenic; Mutation; Myocardium - cytology; Myocardium - metabolism; Phosphatases; Phosphoprotein Phosphatases - metabolism; Phosphorylation; Physiological regulation; Potassium; Potassium - metabolism; Potassium Channels - chemistry; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Voltage-Gated; Protein Phosphatase 1; Proteins; Receptors, Adrenergic, beta - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Signal Transduction; Somatic cells
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1066843

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