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Structural determinants for high-affinity block of hERG potassium channels.
Novartis Found Symp. 2005; 266:136-50; discussion 150-8.NF

Abstract

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).

Authors+Show Affiliations

Department of Cell Physiology and Pharmacology, University of Leicester, University Road, Leicester LE1 9HN, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

16050266

Citation

Mitcheson, John, et al. "Structural Determinants for High-affinity Block of hERG Potassium Channels." Novartis Foundation Symposium, vol. 266, 2005, pp. 136-50; discussion 150-8.
Mitcheson J, Perry M, Stansfeld P, et al. Structural determinants for high-affinity block of hERG potassium channels. Novartis Found Symp. 2005;266:136-50; discussion 150-8.
Mitcheson, J., Perry, M., Stansfeld, P., Sanguinetti, M. C., Witchel, H., & Hancox, J. (2005). Structural determinants for high-affinity block of hERG potassium channels. Novartis Foundation Symposium, 266, 136-50; discussion 150-8.
Mitcheson J, et al. Structural Determinants for High-affinity Block of hERG Potassium Channels. Novartis Found Symp. 2005;266:136-50; discussion 150-8. PubMed PMID: 16050266.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural determinants for high-affinity block of hERG potassium channels. AU - Mitcheson,John, AU - Perry,Matthew, AU - Stansfeld,Phillip, AU - Sanguinetti,Michael C, AU - Witchel,Harry, AU - Hancox,Jules, PY - 2005/7/30/pubmed PY - 2005/8/19/medline PY - 2005/7/30/entrez SP - 136-50; discussion 150-8 JF - Novartis Foundation symposium JO - Novartis Found Symp VL - 266 N2 - 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). SN - 1528-2511 UR - https://www.unboundmedicine.com/medline/citation/16050266/Structural_determinants_for_high_affinity_block_of_hERG_potassium_channels_ L2 - http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=572 DB - PRIME DP - Unbound Medicine ER -