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

Sun X, Zhou D, Zhang P, Moczydlowski EG, Haddad GG. -Subunit–dependent modulation of hSlo BK current by arachidonic acid. J Neurophysiol 97: 62–69, 2007. First published October 4, 2006; doi:10.1152/jn.00700.2006. 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 hSlocurrent 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 hSlo2 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 hSlocurrent, 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.