Polyunsaturated fatty acids inhibit Kv1.4 by interacting with positively charged extracellular pore residues

• Published in: American Journal of Physiology: Cell Physiology 2016-08, Vol.311 (2), p.C255-C268
• Main Authors: Farag, N E, Jeong, D, Claydon, T, Warwicker, J, Boyett, M R
• Format: Article
• Language: English
• Subjects: Acidity; Animals; Fatty acids; Fatty Acids, Unsaturated - metabolism; Hydrogen - metabolism; Ion Channel Gating - physiology; Kv1.4 Potassium Channel - metabolism; Membrane Potentials - physiology; Physiology; Potassium; Potassium - metabolism; Potassium Channels, Voltage-Gated - metabolism; Xenopus laevis - metabolism; Xenopus laevis - physiology
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00277.2015

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.