Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA

Large-conductance Ca2+-and voltage-activated K+ (BK) channels are well known for their functional versatility, which is bestowed in part by their rich modulatory repertoire. We recently showed that long-chain omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) found in oily fish lower blood pressure by activating vascular BK channels made of Slo1+beta 1 subunits. Here we examined the action of DHA on BK channels with different auxiliary subunit compositions. Neuronal Slo1+beta 4 channels were just as well activated by DHA as vascular Slo1+beta 1 channels. In contrast, the stimulatory effect of DHA was much smaller in Slo1+beta 2, Slo1+LRRC26 (gamma 1), and Slo1 channels without auxiliary subunits. Mutagenesis of beta 1, beta 2, and beta 4 showed that the large effect of DHA in Slo1+beta 1 and Slo1+beta 4 is conferred by the presence of two residues, one in the N terminus and the other in the first transmembrane segment of the beta 1 and beta 4 subunits. Transfer of this amino acid pair from beta 1 or beta 4 to beta 2 introduces a large response to DHA in Slo1+beta 2. The presence of a pair of oppositely charged residues at the aforementioned positions in beta subunits is associated with a large response to DHA. The Slo1 auxiliary subunits are expressed in a highly tissue-dependent fashion. Thus, the subunit composition-dependent stimulation by DHA demonstrates that BK channels are effectors of omega-3 fatty acids with marked tissue specificity.