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Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels.
Proc Natl Acad Sci U S A. 2002 Sep 17; 99(19):12461-6.PN

Abstract

Unintended block of HERG K+ channels is a side effect of many common medications and is the most common cause of acquired long QT syndrome associated with increased risk of life-threatening arrhythmias. The molecular mechanism of high-affinity HERG block by structurally diverse compounds has been attributed to pi-stacking and cation-pi interactions of a drug (e.g., cisapride) with specific aromatic amino acid residues (Tyr-652 and Phe-656) in the S6 alpha-helical domain that face the central cavity of the channel. It also has been proposed that strong C-type inactivation of HERG facilitates or is the primary determinant of high-affinity drug binding. The structurally related, but noninactivating eag channel is insensitive to HERG blockers unless inactivation is induced by specific amino acid mutations [Ficker, E., Jarolimek, W. & Brown, A. M. (2001) Mol. Pharmacol. 60, 1343-1348]. Here we examine the relative importance of inactivation vs. positioning of S6 aromatic residues in determining sensitivity of HERG and eag channels to block by cisapride. The repositioning of Tyr-652 or Phe-656 along the S6 alpha-helical domain of HERG reduced sensitivity of channels to block by cisapride. Moreover, independent of inactivation, repositioning of the equivalent aromatic residues in Drosophila eag channels induced sensitivity to block by cisapride. These findings suggest that positioning of S6 aromatic residues relative to the central cavity of the channel, not inactivation per se determines drug block of HERG or eag channels.

Authors+Show Affiliations

Department of Internal Medicine, University of Utah, 15 North 2030 East, Room 4220, Salt Lake City, UT 84112, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12209010

Citation

Chen, Jun, et al. "Position of Aromatic Residues in the S6 Domain, Not Inactivation, Dictates Cisapride Sensitivity of HERG and Eag Potassium Channels." Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 19, 2002, pp. 12461-6.
Chen J, Seebohm G, Sanguinetti MC. Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. Proc Natl Acad Sci U S A. 2002;99(19):12461-6.
Chen, J., Seebohm, G., & Sanguinetti, M. C. (2002). Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. Proceedings of the National Academy of Sciences of the United States of America, 99(19), 12461-6.
Chen J, Seebohm G, Sanguinetti MC. Position of Aromatic Residues in the S6 Domain, Not Inactivation, Dictates Cisapride Sensitivity of HERG and Eag Potassium Channels. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12461-6. PubMed PMID: 12209010.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels. AU - Chen,Jun, AU - Seebohm,Guiscard, AU - Sanguinetti,Michael C, Y1 - 2002/09/03/ PY - 2002/9/5/pubmed PY - 2002/10/29/medline PY - 2002/9/5/entrez SP - 12461 EP - 6 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 99 IS - 19 N2 - Unintended block of HERG K+ channels is a side effect of many common medications and is the most common cause of acquired long QT syndrome associated with increased risk of life-threatening arrhythmias. The molecular mechanism of high-affinity HERG block by structurally diverse compounds has been attributed to pi-stacking and cation-pi interactions of a drug (e.g., cisapride) with specific aromatic amino acid residues (Tyr-652 and Phe-656) in the S6 alpha-helical domain that face the central cavity of the channel. It also has been proposed that strong C-type inactivation of HERG facilitates or is the primary determinant of high-affinity drug binding. The structurally related, but noninactivating eag channel is insensitive to HERG blockers unless inactivation is induced by specific amino acid mutations [Ficker, E., Jarolimek, W. & Brown, A. M. (2001) Mol. Pharmacol. 60, 1343-1348]. Here we examine the relative importance of inactivation vs. positioning of S6 aromatic residues in determining sensitivity of HERG and eag channels to block by cisapride. The repositioning of Tyr-652 or Phe-656 along the S6 alpha-helical domain of HERG reduced sensitivity of channels to block by cisapride. Moreover, independent of inactivation, repositioning of the equivalent aromatic residues in Drosophila eag channels induced sensitivity to block by cisapride. These findings suggest that positioning of S6 aromatic residues relative to the central cavity of the channel, not inactivation per se determines drug block of HERG or eag channels. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/12209010/Position_of_aromatic_residues_in_the_S6_domain_not_inactivation_dictates_cisapride_sensitivity_of_HERG_and_eag_potassium_channels_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12209010 DB - PRIME DP - Unbound Medicine ER -