S641 contributes HERG K+ channel inactivation

Jin Song Bian, Jie Cui, Yonathan Melman, Thomas V. McDonald

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The kinetics of voltage-dependent inactivation of the rapidly activating delayed rectifier, IKr, are unique among K+ channels. The human ether-a-gogo-related gene (HERG) encodes the pore-forming subunit of IKr and shares a high degree of homology with ether-a-gogo (EAG) channels that do not inactivate. Within those segments thought to contribute to the channel pore, HERG possesses several serine residues that are not present in EAG channels. Two of these serines, S620 and S631, are known to be required for inactivation. We now show that a third serine, S641, which resides in the outer portion of the sixth transmembrane segment, is also critical for normal inactivation. As with the other serines, S641 is also involved in maintaining ion selectivity of the HERG channel and alters sensitivity to block by E4031. Larger charged or polar substitutions (S641D and S641T) disrupted C-type inactivation in HERG. Smaller aliphatic and more conservative substitutions (S641A and S641C) facilitated C-type inactivation. Our data show that, like S620 and S631, S641 is another key residue for the rapid inactivation. The altered inactivation of mutations at S620, S631, and S641 were dominant, suggesting that a network of hydroxyl side chains is required for the unique inactivation, permeation, and rectification of HERG channels.

Original languageEnglish (US)
Pages (from-to)25-39
Number of pages15
JournalCell Biochemistry and Biophysics
Volume41
Issue number1
StatePublished - Aug 2004

Fingerprint

Ether
Genes
Serine
Substitution reactions
Permeation
Hydroxyl Radical
Ions
Mutation
Kinetics
Electric potential

Keywords

  • Channel gating
  • Delayed recifier
  • Electrophysiology
  • HERG
  • Long QT syndrome
  • Mutagenesis
  • Potassium channel
  • Protein structure
  • Voltage-gated channel

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Biophysics

Cite this

Bian, J. S., Cui, J., Melman, Y., & McDonald, T. V. (2004). S641 contributes HERG K+ channel inactivation. Cell Biochemistry and Biophysics, 41(1), 25-39.

S641 contributes HERG K+ channel inactivation. / Bian, Jin Song; Cui, Jie; Melman, Yonathan; McDonald, Thomas V.

In: Cell Biochemistry and Biophysics, Vol. 41, No. 1, 08.2004, p. 25-39.

Research output: Contribution to journalArticle

Bian, JS, Cui, J, Melman, Y & McDonald, TV 2004, 'S641 contributes HERG K+ channel inactivation', Cell Biochemistry and Biophysics, vol. 41, no. 1, pp. 25-39.
Bian JS, Cui J, Melman Y, McDonald TV. S641 contributes HERG K+ channel inactivation. Cell Biochemistry and Biophysics. 2004 Aug;41(1):25-39.
Bian, Jin Song ; Cui, Jie ; Melman, Yonathan ; McDonald, Thomas V. / S641 contributes HERG K+ channel inactivation. In: Cell Biochemistry and Biophysics. 2004 ; Vol. 41, No. 1. pp. 25-39.
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N2 - The kinetics of voltage-dependent inactivation of the rapidly activating delayed rectifier, IKr, are unique among K+ channels. The human ether-a-gogo-related gene (HERG) encodes the pore-forming subunit of IKr and shares a high degree of homology with ether-a-gogo (EAG) channels that do not inactivate. Within those segments thought to contribute to the channel pore, HERG possesses several serine residues that are not present in EAG channels. Two of these serines, S620 and S631, are known to be required for inactivation. We now show that a third serine, S641, which resides in the outer portion of the sixth transmembrane segment, is also critical for normal inactivation. As with the other serines, S641 is also involved in maintaining ion selectivity of the HERG channel and alters sensitivity to block by E4031. Larger charged or polar substitutions (S641D and S641T) disrupted C-type inactivation in HERG. Smaller aliphatic and more conservative substitutions (S641A and S641C) facilitated C-type inactivation. Our data show that, like S620 and S631, S641 is another key residue for the rapid inactivation. The altered inactivation of mutations at S620, S631, and S641 were dominant, suggesting that a network of hydroxyl side chains is required for the unique inactivation, permeation, and rectification of HERG channels.

AB - The kinetics of voltage-dependent inactivation of the rapidly activating delayed rectifier, IKr, are unique among K+ channels. The human ether-a-gogo-related gene (HERG) encodes the pore-forming subunit of IKr and shares a high degree of homology with ether-a-gogo (EAG) channels that do not inactivate. Within those segments thought to contribute to the channel pore, HERG possesses several serine residues that are not present in EAG channels. Two of these serines, S620 and S631, are known to be required for inactivation. We now show that a third serine, S641, which resides in the outer portion of the sixth transmembrane segment, is also critical for normal inactivation. As with the other serines, S641 is also involved in maintaining ion selectivity of the HERG channel and alters sensitivity to block by E4031. Larger charged or polar substitutions (S641D and S641T) disrupted C-type inactivation in HERG. Smaller aliphatic and more conservative substitutions (S641A and S641C) facilitated C-type inactivation. Our data show that, like S620 and S631, S641 is another key residue for the rapid inactivation. The altered inactivation of mutations at S620, S631, and S641 were dominant, suggesting that a network of hydroxyl side chains is required for the unique inactivation, permeation, and rectification of HERG channels.

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