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

Authors

  • Plamena Angelova,

    1. Neuroscience Research Institute, Charité, Humboldt University, Berlin, Germany
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  • Wolfgang Müller

    1. Neuroscience Research Institute, Charité, Humboldt University, Berlin, Germany
    2. Departments of Neurosurgery, Neurology and Neuroscience, University of New Mexico School of Medicine, 2nd Floor ACC, MSC 105610, 1 University of New Mexico, Albuquerque, NM 87131–5341, USA
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: Dr Wolfgang Müller, 2Departments of Neurosurgery, Neurology and Neuroscience, as above.
E-mail: wmueller@salud.unm.edu

Abstract

Oxidative stress affects cellular membrane lipids and proteins. Using whole-cell patch-clamp recording we demonstrate differential oxidative inhibition of voltage-gated transient (IA) and delayed rectifier [IK(V)] K+ currents by arachidonic acid (AA) and H2O2 in CA1 neurons in hippocampal slice. We show that intracellular application of 1 pm AA or its non-metabolizable analog eicosatetraynoic acid (100 pm) reduced IA by ∼42% but did not affect IK(V). AA shifted the voltage dependence of steady-state inactivation of IA by 12 mV to more negative potentials whereas the rate of inactivation was unchanged. Surprisingly, intracellular glutathione (GSH, 20 mm) enhanced the effect of AA on maximal IA (−62%) and with AA slowed inactivation of IA. The combination of GSH and extracellular ascorbate (0.4 mm) prevented reduction of IA by AA. Intracellular Trolox (a vitamin E analog, 10 µm) reduced IA by 61%and IK(V) by 39%. Like AA, intracellular Trolox caused a 10-mV left shift of IA steady-state inactivation but Trolox and AA did not cause a shift when coapplied. Extracellular Trolox (100 µm) had no effects on IA. H2O2 (80 µm) reduced both IA and IK(V) in a GSH- and ascorbate-sensitive manner and slowed the rate of inactivation of IA by a factor of 2. Coapplication of H2O2 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 IA by oxidative modifications. Antioxidants can augment these effects, probably by catalysis of the underlying reactions between oxidants and IA channel proteins.

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