The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations
Autor: | Shuxia Zhao, Arthur M. Brown, Eckhard Ficker, Carlos A. Obejero-Paz |
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Rok vydání: | 2002 |
Předmět: |
ERG1 Potassium Channel
Protein Folding Patch-Clamp Techniques Potassium Channels Pyridines Mutant Pharmacology medicine.disease_cause Biochemistry Piperidines Cation Transport Proteins Cisapride Mutation biology Quinidine Cell biology DNA-Binding Proteins Electrophysiology Long QT Syndrome Potassium Channels Voltage-Gated Histamine H1 Antagonists Anti-Arrhythmia Agents congenital hereditary and neonatal diseases and abnormalities Long QT syndrome Blotting Western hERG Cell Line Inhibitory Concentration 50 Structure-Activity Relationship Gastrointestinal Agents Transcriptional Regulator ERG medicine Humans Channel blocker cardiovascular diseases Binding site Molecular Biology Ions Binding Sites Dose-Response Relationship Drug Endoplasmic reticulum Cell Membrane Wild type Cell Biology Astemizole medicine.disease Ether-A-Go-Go Potassium Channels Quaternary Ammonium Compounds Models Chemical Mutagenesis Site-Directed Trans-Activators biology.protein Benzimidazoles |
Zdroj: | Journal of Biological Chemistry. 277:4989-4998 |
ISSN: | 0021-9258 |
DOI: | 10.1074/jbc.m107345200 |
Popis: | Mutations in the human ether-a-gogo-related gene (HERG) K(+) channel gene cause chromosome 7-linked long QT syndrome type 2 (LQT2), which is characterized by a prolonged QT interval in the electrocardiogram and an increased susceptibility to life-threatening cardiac arrhythmias. LQT2 mutations produce loss-of-function phenotypes and reduce I(Kr) currents either by the heteromeric assembly of non- or malfunctioning channel subunits with wild type subunits at the cell surface or by retention of misprocessed mutant HERG channels in the endoplasmic reticulum. Misprocessed mutations often encode for channel proteins that are functional upon incorporation into the plasma membrane. As a result the pharmacological correction of folding defects and restoration of protein function are of considerable interest. Here we report that the trafficking-deficient pore mutation HERG G601S was rescued by a series of HERG channel blockers that increased cell surface expression. Rescue by these pharmacological chaperones varied directly with their blocking potency. We used structure-activity relationships and site-directed mutagenesis to define the binding site of the pharmacological chaperones. We found that binding occurred in the inner cavity and correlated with hydrophobicity and cationic charge. Rescue was domain-restricted because the trafficking of two misprocessed mutations in the C terminus, HERG F805C and HERG R823W, was not restored by channel blockers. Our findings represent a first step toward the design of pharmacological chaperones that will rescue HERG K(+) channels without block. |
Databáze: | OpenAIRE |
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