Oxidative modulation of the transient potassium current I A by intracellular arachidonic acid in rat CA1 pyramidal neurons

Oxidative stress affects cellular membrane lipids and proteins. Using whole‐cell patch‐clamp recording we demonstrate differential oxidative inhibition of voltage‐gated transient (I A ) and delayed rectifier [I K(V) ] K + currents by arachidonic acid (AA) and H 2 O 2 in CA1 neurons in hippocampal slice. We show that intracellular application of 1 p m AA or its non‐metabolizable analog eicosatetraynoic acid (100 p m ) reduced I A by ∼42% but did not affect I K(V) . AA shifted the voltage dependence of steady‐state inactivation of I A by 12 mV to more negative potentials whereas the rate of inactivation was unchanged. Surprisingly, intracellular glutathione (GSH, 20 m m ) enhanced the effect of AA on maximal I A (−62%) and with AA slowed inactivation of I A . The combination of GSH and extracellular ascorbate (0.4 m m ) prevented reduction of I A by AA. Intracellular Trolox (a vitamin E analog, 10 µ m ) reduced I A by 61%and I K(V) by 39%. Like AA, intracellular Trolox caused a 10‐mV left shift of I A steady‐state inactivation but Trolox and AA did not cause a shift when coapplied. Extracellular Trolox (100 µ m ) had no effects on I A . H 2 O 2 (80 µ m ) reduced both I A and I K(V) in a GSH‐ and ascorbate‐sensitive manner and slowed the rate of inactivation of I A by a factor of 2. Coapplication of H 2 O 2 with GSH and extracellular ascorbate caused ∼22 mV negative shifts of both steady‐state inactivation and activation. We conclude that AA is extremely potent in affecting I A by oxidative modifications. Antioxidants can augment these effects, probably by catalysis of the underlying reactions between oxidants and I A channel proteins.