8.A.14 The Ca²⁺-activated K⁺ Channel auxiliary subunit Slowpoke-β (Sloβ) Family

The Sloβ (slowpoke, subunit β) family is a relatively small family of vertebrate homologues. The principal subunit (α) is the large conductance Ca²⁺-activated BK K⁺ channel (TC #1.A.1.3.1), which requires both Ca²⁺ and voltage for opening. Sloβ possesses 2 TMSs in its N- and C-termini, bearing phosphorylation sites in the cytoplasm. The extracellular loop is glycosylated. The Sloβ subunit regulates sensitivity to voltage and Ca²⁺. It may enhance Ca²⁺ sensitivity by altering the conformation and movements of the voltage sensor. A similar function of the beta2 subunit may be governed by a distinct mechanism (Yang et al., 2008).

Regulation of voltage-activated K⁺ channel gating by transmembrane β-subunits has been reviewed (Sun et al., 2012). The beta2 subunit of BKCa modulates the apparent Ca²⁺/voltage sensitivity as well as the pharmacological and kinetic properties of the channel. In addition, the N terminus of the beta2 subunit acts as an inactivating particle that produces a relatively fast inactivation of the ionic conductance. Thus, the beta2 subunit of BKCa channels facilitates channel activation by changing the voltage sensor equilibrium, and this is followed by beta(2)-induced inactivation (Savalli et al. 2007).

Coded by a single gene (Slo1, KCM) BK channels are activated by depolarizing potentials and by a rise in intracellular Ca²⁺ concentration.  They are large conductance voltage- and Ca²⁺-activated K⁺ channel tetramers characterized by a pore-forming alpha subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K⁺ channels) and a large C-terminus composed of two  K⁺ conductance regulatory domains (RCK domains), where the Ca²⁺-binding sites reside. BK channels are associated with accessory beta subunits, and four beta subunits are known (beta1, beta2, beta3, and beta4). Despite the fact that they all share the same topology, each beta subunit has a specific tissue distribution, modifies channel kinetics distinctively, exhibits different pharmacological properties and has different Ca²⁺ sensitivities (Torres et al. 2014).

Beta1 plays an important role in the modulation of arterial tone and blood pressure by vascular smooth muscle cells (SMCs). 17beta-estradiol (E2) increases the BK channel open probability (Po) in SMCs, through a beta1 subunit- dependent modulatory effect. Granados et al. 2019 identified a cluster of hydrophobic residues in the second TMS of beta1, including the residues W163 and F166, as the binding site for E2. The increase in Po induced by E2 is associated with stabilization of the voltage sensor in its active configuration and an increase in the coupling between voltage sensor activation and pore opening (Granados et al. 2019).

The transport reaction catalyzed by the BK channel αβ complex is:

K⁺ (in) K⁺ (out)