Structural determinants for high-affinity block of hERG potassium channels.
Drug-induced long QT syndrome is an abnormality of cardiac action potential repolarization that can induce arrhythmias and sudden death. This unwanted side effect of some medications is most frequently associated with block of hERG channels, even though it could theoretically result from inhibition of any K+ current with a role in repolarization. Recent studies suggest an explanation for why so many structurally diverse compounds preferentially block hERG. State dependent inhibition of hERG channel currents and slow kinetics for recovery from block suggest that many drugs bind within the inner cavity of the channel and are trapped by closure of the activation gate upon repolarization. Drug trapping studies indicate that the inner cavity of hERG is larger than other voltage-gated K+ channels. Scanning Ala mutagenesis of S6 and pore helix domains that line the inner cavity of hERG have demonstrated that two aromatic residues (Tyr652 and Phe656) are important sites of interaction for most blockers investigated so far. These residues are unique to the EAG channel family. Ser624 and Thr623 residues at the base of the pore helices are also critical for high-affinity binding for some compounds (e.g. methanesulfonanilides) but not others (cisapride, terfenadine, propafenone).
Mitcheson
John
J
Department of Cell Physiology and Pharmacology, University of Leicester, University Road, Leicester LE1 9HN, UK.
Perry
Matthew
M
Stansfeld
Phillip
P
Sanguinetti
Michael C
MC
Witchel
Harry
H
Hancox
Jules
J
D000200:Action Potentials / Q000187:drug effects*; D000595:Amino Acid Sequence; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated