Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel

Susan I.V. Judge*, Mervyn J. Monteiro, Jay Z. Yeh, Christopher T. Bever

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Voltage-gated K+ channels vary in sensitivity to block by 4- aminopyridine (4-AP) over a 1000-fold range. Most K+ channel phenotypes with leucine at the fourth position (L4) in the leucine heptad repeat region, spanning the S4-S5 linker, exhibit low 4-AP sensitivity, while channels with phenylalanine exhibit high sensitivity. Mutational analysis on delayed rectifier type K+ channels demonstrate increased 4-AP sensitivity upon mutation of the L4 heptad leucine to phenylalanine. This mutation can also influence inactivation gating, which is known to compete with 4-AP in rapidly inactivating A-type K+ channels. Here, in a rapidly inactivating human brain Kv1.4 channel, we demonstrate a 400-fold increase in 4-AP sensitivity following substitution of L4 with phenylalanine. Accompanying this mutation is a slowing of inactivation, an acceleration of deactivation, and depolarizing shifts in the voltage dependence of activation and steady-state inactivation. To test the relative role of fast inactivation in modulating 4- AP block, N-terminal deletions of the fast inactivation gate were carded out in both channels. These deletions produced no change in 4-AP sensitivity in the mutant channel and approximately a six-fold increase in the wild type channel. These results support the view that changes at L4 which increase 4- AP sensitivity are largely due to 4-AP binding and may, in part, arise from alterations in channel conformation. Primarily, this study demonstrates that the fast inactivation gate is not a critical determinant of 4-AP sensitivity in Kv1.4 channels.

Original languageEnglish (US)
Pages (from-to)43-54
Number of pages12
JournalBrain research
Volume831
Issue number1-2
DOIs
StatePublished - Jun 12 1999

Keywords

  • 4-Aminopyridine
  • Fast inactivation gate
  • Kv1.4 potassium channel
  • L4 heptad leucine
  • Mutagenesis
  • N-terminus deletion

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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