Beta-subunit-dependent modulation of hSlo BK current by arachidonic acid.
In this study, we examined the effect of arachidonic acid (AA) on the BK alpha-subunit with or without beta-subunits expressed in Xenopus oocytes. In excised patches, AA potentiated the hSlo-alpha current and slowed inactivation only when beta2/3 subunit was co-expressed. The beta2-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-alpha + beta2 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 beta2-ball peptide induced inactivation of the hSlo-alpha 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 beta2 to prevent the inactivation ball from reaching its receptor. Our data reveal a novel mechanism of beta-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.
Sun
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Department of Pediatrics, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92037-0735, USA.
Zhou
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Zhang
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P
Moczydlowski
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EG
Haddad
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GG
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
D005231:Fatty Acids, Unsaturated; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D021122:Protein Subunits; D016718:Arachidonic Acid