Kinetic modulation of Kv4-mediated A-current by arachidonic acid is dependent on potassium channel interacting proteins

The Kv4 subfamily of voltage-gated potassium channels is responsible for th e transient A-type potassium current that operates at subthreshold membrane potentials to control membrane excitability. Arachidonic acid was shown re cently 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 result s suggest the existence of Kv4 auxiliary subunit(s) in native cells. We rep ort here a K-channel interacting protein (KChIP)-dependent kinetic modulati on of Kv4.2 current in Chinese hamster ovary cells and Kv4.2 and Kv4.3 curr ents in Xenopus oocytes by arachidonic acid at physiological concentrations . This concentration-dependent effect of arachidonic acid resembled that ob served in cerebellar granule neurons and was fully reversible. Other fatty acids, including a nonhydrolyzable inhibitor of both lipooxygenase and cycl ooxygenase, 5,8,11,14-eicosatetraynoic acid (ETYA), also mimicked arachidon ic acid in modulating Kv4.3 and Kv4.3/KChIP1 currents. Compared with anothe r transient potassium current formed by Kv1.1/Kv beta1, Kv4.3/ KChIP1 curre nt was much more sensitive to arachidonic acid. Association between KChIP1 and Kv4.2 or Kv4.3 was not altered in the presence of 10 muM ETYA as measur ed by immunoprecipitation and association-dependent growth in yeast. Our da ta suggest that the KChIP proteins represent a molecular entity for the obs erved difference between arachidonic acid effects on A-current kinetics in heterologous cells and in native cells and are consistent with the notion t hat KChIP proteins modulate the subthreshold A-current in neurons.