Modulation of BKCa channel activity by fatty acids:: structural requirements and mechanism of action

To determine the mechanism of fatty acid modulation of rabbit pulmonary artery large-conductance Ca(2+-)activated K+ (BKCa) channel activity, we studied effects of fatty acids and other lipids on channel activity in excised patches with patch-clamp techniques. The structural features of the fatty acid required to increase BKCa channel activity (or average number of open channels, NPo) were identified to be the negatively charged head group and a sufficiently long (C > 8) carbon chain. Positively charged lipids like sphingosine, which have a sufficiently long alkyl chain (C greater than or equal to 8), produced a decrease in NPo. Neutral and short-chain lipids did not alter NPo. Screening of membrane surface charge with high-ionic-strength bathing solutions (330 mM K+ or 130 mM K+, 300 mM Na+) did not alter the modulation of the BKCa channel NPo by fatty acids and other charged lipids, indicating that channel modulation is unlikely to be due to an alteration of the membrane electric field or the attraction of local counterions to the channel. Fatty acids and other negatively charged lipids were able to modulate BKCa channel activity in bathing solutions containing 0 mM Ca2+, 20 mM EGTA, suggesting that calcium is not required for this modulation. Together, these results indicate that modulation of BKCa channels by fatty acids and other charged lipids most likely occurs by their direct interaction with the channel protein itself or with some other channel-associated component.