Arachidonic acid potently inhibits both postsynaptic-type Kv4.2 and presynaptic-type Kv1.4 IA potassium channels

Arachidonic acid (AA) is a free fatty acid membrane-permeable second messenger that is liberated from cell membranes via receptor- and Ca2+-dependent events. We have shown previously that extremely low [AA](i) (1 pm) inhibits the postsynaptic voltage-gated K+ current (I-A) in hippocampal neurons. This inhibition is blocked by some antioxidants. The somatodendritic I-A is mediated by Kv4.2 gene products, whereas presynaptic I-A is mediated by Kv1.4 channel subunits. To address the interaction of AA with these alpha-subunits we studied the modulation of A-currents in human embryonic kidney 293 cells transfected with either Kv1.4 or Kv4.2 rat cDNA, using whole-cell voltage-clamp recording. For both currents 1 pm [AA](i) inhibited the conductance by > 50%. In addition, AA shifted the voltage dependence of inactivation by -9 (Kv1.4) and +6 mV (Kv4.2), respectively. Intracellular co-application of Trolox C (10 mu m), an antioxidant vitamin E derivative, only slowed the effects of AA on amplitude. Notably, Trolox C shifted the voltage dependence of activation of Kv1.4-mediated I-A by -32 mV. Extracellular Trolox for > 15 min inhibited the AA effects on I-A amplitudes as well as the effect of intracellular Trolox on the voltage dependence of activation of Kv1.4-mediated I-A. Extracellular Trolox further shifted the voltage dependence of activation for Kv4.2 by +33 mV. In conclusion, the inhibition of maximal amplitude of Kv4.2 channels by AA can explain the inhibition of somatodendritic I-A in hippocampal neurons, whereas the negative shift in the voltage dependence of inactivation apparently depends on other neuronal channel subunits. Both AA and Trolox potently modulate Kv1.4 and Kv4.2 channel alpha-subunits, thereby presumably tuning presynaptic transmitter release and postsynaptic somatodendritic excitability in synaptic transmission and plasticity.