A hydrophobicity-dependent motif responsible for surface expression of cardiac potassium channel |
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| Authors: | Na Pan Jing Sun Caixia Lv Hui Li Jiuping Ding |
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| Institution: | 1. Department of Physiology & Biophysics, Virginia Commonwealth University, Richmond, Virginia;2. Department of Medicine, Pulmonary Section, University of Illinois at Chicago, Illinois;3. Department of Chemistry, University of Illinois at Chicago, Illinois;4. Department of Biology, University of Erlangen-Nürnberg, Erlangen, Germany;1. Department of Molecular Pharmacology, Medical Faculty of the RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany;2. Grünenthal GmbH, Global Drug Discovery, Department of Molecular Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany;1. Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA;2. Department of Pharmacology, Georgia Regents University, Augusta, GA 30912, USA;1. Laboratoire des Venins et de Molécules Thérapeutiques, Institut Pasteur Tunis, University Tunis El Manar, 13 Place Pasteur, BP-74, 1002 Tunis, Tunisia;2. Laboratory for Molecular Biophysics, Physiology, and Pharmacology, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;3. Service des unités animalières, Institut Pasteur Tunis, Tunisia;4. Laboratory of Cellular and MolecularImmunology, VrijeUniversiteit Brussel, Brussels, Belgium;5. Faculté de Médecine de Tunis, Université Tunis El Manar, Tunisia |
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| Abstract: | The long-QT syndrome (LQTS) is an inherited cardiac disorder associated with syncope and a high risk of sudden death. The molecular basis of type-1 LQTS (LQT1) is a missense or nonsense mutation in KCNQ channels that reduces slowly activating delayed rectifier potassium channel (IKs) resulting in a prolonged action potential. Noticeably, the S2–S3 linker is a highly congregating region of LQT1 mutations. To further explore the mechanism, a KCNQ mutant (L191P) identified in one Chinese pedigree with LQT1 was chosen for this purpose. As Leu-191 is located in the middle of a well-known endoplasmic reticulum (ER) localization signal (RXR) in the intracellular S2–S3 linker, we examined the kinetics and the surface expression of both the KCNQ1 and L191 mutants. Our results showed that the mutation did not affect the channel kinetics, whereas the surface expression increased with increasing hydrophobicity of the middle residue ‘X’ of the RXR motif. Based on an analysis of fractional fluorescence data using a binomial model, we also found that the percentage of KCNQ1/L191P heteromeric channels expressed at the cell surface were 22.0%, 40.5%, 27.9%, 8.6% and 1.0% of heteromeric channels with 0, 1, 2, 3 and 4 subunits of L191P, respectively, in a transfected ratio of KCNQ1: L191P = 1:1. These experiments demonstrated that coexpression of L191P resulted in a trafficking factor α < 1, causing a trafficking deficiency of heteromeric channels that underlay the dominant-negative effect. This study suggests several trafficking signals coexisting in this region, and expands our understanding of possible dominant-negative mechanisms underlying LQTS. |
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