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-Subunit–Dependent Modulation of hSlo BK Current by Arachidonic Acid

¹Departments of Pediatrics and ²Neuroscience, University of California San Diego, La Jolla, California; ³Department of Physiology, Yale University, New Haven, Connecticut; and ⁴Department of Biology, Clarkson University, Potsdam, New York

Submitted 6 July 2006; accepted in final form 28 September 2006

In this study, we examined the effect of arachidonic acid (AA) on the BK -subunit with or without -subunits expressed in Xenopus oocytes. In excised patches, AA potentiated the hSlo- current and slowed inactivation only when 2/3 subunit was co-expressed. The 2-subunit–dependent modulation by AA persisted in the presence of either superoxide dismutase or inhibitors of AA metabolism such as nordihydroguaiaretic acid and eicosatetraynoic acid, suggesting that AA acts directly rather than through its metabolites. Other cis unsaturated fatty acids (docosahexaenoic and oleic acid) also enhanced hSlo- + 2 currents and slowed inactivation, whereas saturated fatty acids (palmitic, stearic, and caprylic acid) were without effect. Pretreatment with trypsin to remove the cytosolic inactivation domain largely occluded AA action. Intracellularly applied free synthetic 2-ball peptide induced inactivation of the hSlo- current, and AA failed to enhance this current and slow the inactivation. These results suggest that AA removes inactivation by interacting, possibly through conformational changes, with 2 to prevent the inactivation ball from reaching its receptor. Our data reveal a novel mechanism of -subunit–dependent modulation of BK channels by AA. In freshly dissociated mouse neocortical neurons, AA eliminated a transient component of whole cell K⁺ currents. BK channel inactivation may be a specific mechanism by which AA and other unsaturated fatty acids influence neuronal death/survival in neuropathological conditions.

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