Structural Basis forEther-a-go-go-Related Gene K+Channel Subtype-Dependent Activation by Niflumic Acid
| Autor: | David Fernandez, John D. Sargent, Michael C. Sanguinetti, Frank B. Sachse |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
ERG1 Potassium Channel
Time Factors Stereochemistry Recombinant Fusion Proteins Molecular Sequence Data Xenopus Gating Article Structure-Activity Relationship Xenopus laevis Extracellular medicine Animals Humans Computer Simulation Amino Acid Sequence Ion channel Pharmacology Dose-Response Relationship Drug biology Chemistry Anti-Inflammatory Agents Non-Steroidal Cell Membrane Niflumic acid Niflumic Acid biology.organism_classification Ether-A-Go-Go Potassium Channels Potassium channel Rats Potassium Channels Voltage-Gated Oocytes Molecular Medicine Extracellular Space Ion Channel Gating Erg medicine.drug |
| Zdroj: | Molecular Pharmacology. 73:1159-1167 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.107.043505 |
| Popis: | Niflumic acid [2-((3-(trifluoromethyl)phenyl)amino)-3-pyridinecarboxylic acid, NFA] is a nonsteroidal anti-inflammatory drug that also blocks or modulates the gating of a wide spectrum of ion channels. Here we investigated the mechanism of channel activation by NFA on ether-a-go-go-related gene (ERG) K(+) channel subtypes expressed in Xenopus laevis oocytes using two-electrode voltage-clamp techniques. NFA acted from the extracellular side of the membrane to differentially enhance ERG channel currents independent of channel state. At 1 mM, NFA shifted the half-point for activation by -6, -18, and -11 mV for ERG1, ERG2, and ERG3 channels, respectively. The half-point for channel inactivation was shifted by +5 to +9 mV by NFA. The structural basis for the ERG subtype-specific response to NFA was explored with chimeric channels and site-directed mutagenesis. The molecular determinants of enhanced sensitivity of ERG2 channels to NFA were isolated to an Arg and a Thr triplet in the extracellular S3-S4 linker. |
| Databáze: | OpenAIRE |
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