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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)

References associated with 8.A.14 family:

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Bukiya, A.N., A.K. Singh, A.L. Parrill, and A.M. Dopico. (2011). The steroid interaction site in transmembrane domain 2 of the large conductance, voltage- and calcium-gated potassium (BK) channel accessory β1 subunit. Proc. Natl. Acad. Sci. USA 108: 20207-20212. 22123969
Coetzee, W.A., Y. Amalillo, J. Chiu, A. Chow, D. Lau, T. McCormack, H. Moreno, M.S. Nadal, A. Ozaita, D. Pountney, M. Saganich, E. Vega-Saenz de Miera, and B. Rudy (1999). Molecular diversity of K+ channels. Ann. N.Y. Acad. Sci USA 868: 233-285. 10414301
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Hoshi, T., Y. Tian, R. Xu, S.H. Heinemann, and S. Hou. (2013). Mechanism of the modulation of BK potassium channel complexes with different auxiliary subunit compositions by the omega-3 fatty acid DHA. Proc. Natl. Acad. Sci. USA 110: 4822-4827. 23487786
Kuntamallappanavar, G. and A.M. Dopico. (2017). BK β1 Subunit-Dependent Facilitation Of Ethanol Inhibition Of BK Current And Cerebral Artery Constriction Is Mediated By The β1 Transmembrane Domain 2. Br J Pharmacol. [Epub: Ahead of Print] 28940182
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Meera, P., M. Wallner, and L. Toro. (2000). A neuronal beta subunit (KCNMB4) makes the large conductance, voltage- and Ca2+-activated K+ channel resistant to charybdotoxin and iberiotoxin. Proc. Natl. Acad. Sci. USA 97: 5562-5567. 10792058
Prabhu, Y., R. Müller, C. Anjard, and A.A. Noegel. (2007). GrlJ, a Dictyostelium GABAB-like receptor with roles in post-aggregation development. BMC Dev Biol 7: 44. 17501984
Savalli, N., A. Kondratiev, S.B. de Quintana, L. Toro, and R. Olcese. (2007). Modes of operation of the BKCa channel beta2 subunit. J Gen Physiol 130: 117-131. 17591990
Sun, X., M.A. Zaydman, and J. Cui. (2012). Regulation of Voltage-Activated K+ Channel Gating by Transmembrane β Subunits. Front Pharmacol 3: 63. 22529812
Tao, X. and R. MacKinnon. (2019). Molecular structures of the human Slo1 K channel in complex with β4. Elife 8:. 31815672
Tseng-Crank, J., N. Godinot, T.E. Johansen, P.K. Ahring, D. Strøbaek, R. Mertz, C.D. Foster, S.P. Olesen, and P.H. Reinhart. (1996). Cloning, expression, and distribution of a Ca2+-activated K+ channel β-subunit from human brain. Proc. Natl. Acad. Sci. U.S.A. 93: 9200-9205. 8799178
Wallner, M., P. Meera, and L. Toro. (1999). Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane beta-subunit homolog. Proc. Natl. Acad. Sci. U.S.A. 96: 4137-4142. 10097176
Yang, H., G. Zhang, J. Shi, U.S. Lee, K. Delaloye, and J. Cui. (2008). Subunit-specific effect of the voltage sensor domain on Ca2+ sensitivity of BK channels. Biophys. J. 94: 4678-4687. 18339745
Zarei, M.M., M. Song, R.J. Wilson, N. Cox, L.V. Colom, H.G. Knaus, E. Stefani, and L. Toro. (2007). Endocytic trafficking signals in KCNMB2 regulate surface expression of a large conductance voltage and Ca2+-activated K+ channel. Neuroscience 147: 80-89. 17521822