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J Neurophysiol (October 4, 2006). doi:10.1152/jn.00700.2006
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Submitted on July 6, 2006
Accepted on September 28, 2006

{beta}-Subunit-Dependent Modulation of Hslo BK Current by Arachidonic Acid

Xiaolu Sun1, Dan Zhou2, Ping Zhang3, Edward Moczydlowski4, and Gabriel G. Haddad5*

1 Pediatrics, University of California San Diego, Lo Jolla, California, United States
2 Pediatrics, University of California San Diego, La Jolla, California, United States
3 Physiology, Yale University, New Haven, Connecticut, United States
4 Biology, Clarkson University, Potsdam, New York, United States
5 Pediatrics and Neuroscience, University of California San Diego, San Diego, California, United States

* To whom correspondence should be addressed. E-mail: ghaddad{at}ucsd.edu.

In the present study, we examined the effect of Arachidonic Acid 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 {beta}2/3 subunit was co-expressed. The {beta}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 via its metabolites. Other cis unsaturated fatty acids (docosahexaenoic and oleic acid) also enhanced hSlo {alpha}+{beta}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 {beta}2-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 {beta}2 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.




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