Article: Molecular determinants of voltage-dependent human ether-a-go-go related gene (HERG) K+ channel block.
The Journal of biological chemistry
2002 Volume 277, Issue 26, Page(s) 23587–23595
Abstract: ... Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related ... at +40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed ... dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings ...
| Abstract | The structural determinants for the voltage-dependent block of ion channels are poorly understood. Here we investigate the voltage-dependent block of wild-type and mutant human ether-a-go-go related gene (HERG) K(+) channels by the antimalarial compound chloroquine. The block of wild-type HERG channels expressed in Xenopus oocytes was enhanced as the membrane potential was progressively depolarized. The IC(50) was 8.4 +/- 0.9 microm when assessed during 4-s voltage clamp pulses to 0 mV. Chloroquine also slowed the apparent rate of HERG deactivation, reflecting the inability of drug-bound channels to close. Mutation to alanine of aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of HERG greatly reduced the potency of channel block by chloroquine (IC(50) > 1 mm at 0 mV). However, mutation of Tyr-652 also altered the voltage dependence of the block. In contrast to wild-type HERG, block of Y652A HERG channels was diminished by progressive membrane depolarization, and complete relief from block was observed at +40 mV. HERG channel block was voltage-independent when the hydroxyl group of Tyr-652 was removed by mutating the residue to Phe. Together these findings indicate a critical role for Tyr-652 in voltage-dependent block of HERG channels. Molecular modeling was used to define energy-minimized dockings of chloroquine to the central cavity of HERG. Our experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cation-pi and pi-stacking interactions with Tyr-652 and Phe-656 of multiple subunits. |
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| MeSH term(s) | Benzopyrans/pharmacology ; Binding Sites ; Cation Transport Proteins ; Chloroquine/pharmacology ; DNA-Binding Proteins ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; Humans ; Membrane Potentials ; Piperidines/pharmacology ; Potassium Channel Blockers ; Potassium Channels/chemistry ; Potassium Channels/physiology ; Potassium Channels, Voltage-Gated ; Structure-Activity Relationship ; Trans-Activators ; Transcriptional Regulator ERG |
| Chemical Substances | Benzopyrans ; Cation Transport Proteins ; DNA-Binding Proteins ; ERG protein, human ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; KCNH2 protein, human ; KCNH6 protein, human ; Piperidines ; Potassium Channel Blockers ; Potassium Channels ; Potassium Channels, Voltage-Gated ; Trans-Activators ; Transcriptional Regulator ERG ; L 706000 (150481-98-4) ; Chloroquine (886U3H6UFF) |
| Language | English |
| Publishing date | 2002-04-17 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. |
| ZDB-ID | 2997-x |
| ISSN | 1083-351X ; 0021-9258 |
| ISSN (online) | 1083-351X |
| ISSN | 0021-9258 |
| DOI | 10.1074/jbc.M200448200 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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