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The Journal of Neuroscience, June 15, 2001, 21(12):4154-4161
Kinetic Modulation of Kv4-Mediated A-Current by Arachidonic Acid
Is Dependent on Potassium Channel Interacting Proteins
Mats H.
Holmqvist1,
Jie
Cao1,
Maria H.
Knoppers1,
Mark E.
Jurman1,
Peter S.
Distefano1,
Kenneth J.
Rhodes2,
Yu
Xie1, and
W. Frank
An1
1 Millennium Pharmaceuticals Inc., Cambridge,
Massachusetts 02139, and 2 Wyeth-Ayerst Research,
Princeton, New Jersey 08543
The Kv4 subfamily of voltage-gated potassium channels is
responsible for the transient A-type potassium current that operates at
subthreshold membrane potentials to control membrane excitability. Arachidonic acid was shown recently to modulate both the peak amplitude
and kinetics of the hippocampal A-current. However, in
Xenopus oocytes, arachidonic acid only inhibited the
peak amplitude of Kv4 current without modifying its kinetics. These
results suggest the existence of Kv4 auxiliary subunit(s) in native
cells. We report here a K-channel interacting protein (KChIP)-dependent kinetic modulation of Kv4.2 current in Chinese hamster ovary
cells and Kv4.2 and Kv4.3 currents in Xenopus oocytes by
arachidonic acid at physiological concentrations. This
concentration-dependent effect of arachidonic acid resembled that
observed in cerebellar granule neurons and was fully reversible. Other
fatty acids, including a nonhydrolyzable inhibitor of both
lipooxygenase and cyclooxygenase, 5,8,11,14-eicosatetraynoic acid
(ETYA), also mimicked arachidonic acid in modulating Kv4.3 and
Kv4.3/KChIP1 currents. Compared with another transient potassium
current formed by Kv1.1/Kv 1, Kv4.3/KChIP1 current was much more
sensitive to arachidonic acid. Association between KChIP1 and Kv4.2 or
Kv4.3 was not altered in the presence of 10 µM ETYA as
measured by immunoprecipitation and association-dependent growth in
yeast. Our data suggest that the KChIP proteins represent a molecular
entity for the observed difference between arachidonic acid effects on
A-current kinetics in heterologous cells and in native cells and are
consistent with the notion that KChIP proteins modulate the
subthreshold A-current in neurons.
Key words:
arachidonic acid; Kv4; KChIP; fatty acids; inactivation; potassium channel; auxiliary subunit
Copyright © 2001 Society for Neuroscience 0270-6474/01/21124154-08$05.00/0
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