Polyunsaturated fatty acids inhibit Kv1.4 by interacting with positively charged extracellular pore residues.
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.
Cardiovascular Medicine, School of Medicine, University of Manchester, Core Technology Facility, Manchester, United Kingdom;
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Farag
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada; and.
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D
Jeong
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada; and.
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Claydon
Manchester Institute of Biotechnology, The University of Manchester, Manchester, United Kingdom.
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Warwicker
Cardiovascular Medicine, School of Medicine, University of Manchester, Core Technology Facility, Manchester, United Kingdom; mark.boyett@manchester.ac.uk.
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Boyett
D000818:Animals; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006859:Hydrogen / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology; D051665:Kv1.4 Potassium Channel / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D014982:Xenopus laevis / Q000378:metabolism / Q000502:physiology
D005231:Fatty Acids, Unsaturated; D051665:Kv1.4 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D006859:Hydrogen; D011188:Potassium
PUFAs; inactivation; potassium channels