The Modulatory Function of the BK Channel γ1 Subunit is Determined by its Transmembrane Domain

Abstract

BK channels consist of pore-forming, voltage- and Ca2+-sensing α-subunits (BKα), either alone or together with tissue-specific auxiliary β-subunits (β1-β4) or γ-subunits. The newly identified γ-subunits are a group of leucine-rich repeat (LRR)-containing membrane proteins which contain a single transmembrane (TM) segment, a short intracellular C-terminal tail (C-tail), an N-terminal signal peptide, and a relatively large extracellular LRR domain. The γ1 subunit (LRRC26), so far the most potent activator of BK channels, shifts the channel's voltage dependence of activation in the hyperpolarizing direction by ∼140 mV. We investigated the role and mechanism of the γ1 TM domain in BK channel activation. We identified key amino acid residues in the γ1 hydrophobic TM region involved in BK channel activation. We found that a minimum of 3 positively-charged residues on the intracellular sides of TM segment are also required to maintain the γ1 subunit's full modulatory function, which likely act through stabilization of the TM domain for proper association with BK channels. We also found that the single TM segment and its capping charged residues can fully retain the γ1 subunit's BK channel-activating efficacy. We conclude that the TM domain is a major contributor to the potent channel-activating efficacy of the BK channel γ1 subunit.