Polyunsaturated fatty acids inhibit kv1.4 by interacting with positively charged extracellular pore residues

Research output: Contribution to journalArticle

  • Authors:
  • N. E. Farag
  • D. Jeong
  • T. Claydon
  • J. Warwicker
  • M. R. Boyett

Abstract

Polyunsaturated fatty acids (PUFAs) modulate voltage-gated K+ channel inactivation by an unknown site and mechanism. The effects of ω-6 and ω-3 PUFAs were investigated on the heterologously expressed Kv1.4 channel. PUFAs inhibited wild-type Kv1.4 during repetitive pulsing as a result of slowing of recovery from inactivation. In a mutant Kv1.4 channel lacking N-type inactivation, PUFAs reversibly enhanced C-type inactivation (Kd, 15–43 μM). C-type inactivation was affected by extracellular H+ and K+as well as PUFAs and there was an interaction among the three: the effect of PUFAs was reversed during acidosis and abolished on raising K+. Replacement of two positively charged residues in the extracellular pore (H508 and K532) abolished the effects of the PUFAs (and extracellular H+ and K+) on C-type inactivation but had no effect on the lipoelectric modulation of voltage sensor activation, suggesting two separable interaction sites/mechanisms of action of PUFAs. Charge calculations suggest that the acidic head group of the PUFAs raises the pKa of H508 and this reduces the K+ occupancy of the selectivity filter, stabilizing the C-type inactivated state.

Bibliographical metadata

Original languageEnglish
Pages (from-to)C255-C268
JournalAmerican Journal of Physiology: Cell Physiology
Volume311
Issue number2
DOIs
StatePublished - 1 Aug 2016