Mutational Analysis of Block and Facilitation of HERG Current by A Class III Anti-Arrhythmic Agent, Nifekalant
| Autor: | Atsushi Inanobe, Narutoshi Kamiya, Kengo Kinoshita, Miki Iwata, Yoshihisa Kurachi, Hiroshi Hibino, Mitsuhiko Yamada, Yoshifumi Fukunishi, Kenji Tsujimae, Yukio Hosaka, Haruki Nakamura, Yoshihusa Aizawa |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular ERG1 Potassium Channel Time Factors Protein Conformation hERG Biophysics Pyrimidinones Pharmacology medicine.disease_cause Biochemistry Nifekalant Membrane Potentials Xenopus laevis Potassium Channel Blockers medicine Animals Humans Computer Simulation Ion channel Mutation biology Chemistry Mutagenesis Gene Transfer Techniques Ether-A-Go-Go Potassium Channels Potassium channel Helix Mutagenesis Site-Directed Oocytes Potassium Facilitation biology.protein Anti-Arrhythmia Agents medicine.drug |
| Zdroj: | Channels. 1:198-208 |
| ISSN: | 1933-6969 1933-6950 |
| Popis: | Chemicals and toxins are useful tools to elucidate the structure-function relationship of various proteins including ion channels. The HERG channel is blocked by many compounds and this may cause life-threatening cardiac arrhythmia. Besides block, some chemicals such as the class III anti-arrhythmic agent nifekalant stimulate HERG at low potentials by shifting its activation curve towards hyperpolarizing voltages. This is called "facilitation". Here, we report mutations and simulations analyzing the association between nifekalant and channel pore residues for block and facilitation. Alanine-scanning mutagenesis was performed in the pore region of HERG. The mutations at the base of the pore helix (T623A), the selectivity filter (V625A) and the S6 helix (G648A, Y652A and F656A) abolished and S624A attenuated both block and facilitation induced by the drug. On the other hand, the mutation of other residues caused either an increase or a decrease in nifekalant-induced facilitation without affecting block. An open-state homology model of the HERG pore suggested that T623, S624, Y652 and F656 faced the central cavity, and were positioned within geometrical range for the drug to be able to interact with all of them at the same time. Of these, S649 was the only polar residue located within possible interaction distance from the drug held in its blocking position. Further mutations and flexible-docking simulations suggest that the size, but not the polarity, of the side chain at S649 is critical for drug induced facilitation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|