Investigation of BK Channel Gating using Mallotoxin

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While large-conductance, BK K+ channels are activated by both voltage and by Ca2+ in the microM range, the channels can be activated by voltage even in the absence of Ca2+. BK channel β-subunits, several chemicals, and mutations can shift voltage activation toward more hyperpolarized potentials but in a rather complex manner. In contrast the accessory protein leucine-rich repeat containing protein 26 (LRRC26) and mallotoxin each appears to produce a simple shift. We have investigated the functional basis for the gating shift produced by mallotoxin in the absence and presence of the LRRC26 protein in the context of the Horrigan-Aldrich (HA) model. In the absence of intracellular Ca2+, we found that, in addition to a hyperpolarizing shift of BK activation, mallotoxin produced a large, hyperpolarizing shift of channel activation kinetics. This result suggests that a major action of mallotoxin is to sensitize the BK channel voltage sensors. We also found that the degree of gating shift of mallotoxin was significantly decreased when co-expressed with the LRRC26 protein or in native parotid acinar cells that endogenously express this accessory protein. These results suggest that there is limit to the degree of sensitization of the BK channel voltage sensors.