Pharmacological consequences of the coexpression of BK channel α and auxiliary β subunits

Abstract

Coded by a single gene (Slo1, KCM) and activated by depolarizing potentials and by a rise in intracellular Ca(2+) concentration, the large conductance voltage- and Ca(2+)-activated K(+) channel (BK) is unique among the superfamily of K(+) channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K(+) channels) and a large C terminus composed of two regulators of K(+) conductance domains (RCK domains), where the Ca(2+)-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3, and β4) and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca(2+) sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous, and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above.

Keywords: BK channel; BK pharmacology; BK β subunits; KCNMB; Slo1; auxiliary subunits.

Figure 1

Topological representation of the human Calcium-activated potassium channel α subunit. Using Protter visualizator (Omasits et al., 2014), UniProt protein accession: Q12791.

Figure 2

Human calcium-activated potassium channel β subunit alignment. Using MUSCLE software (Edgar, 2004). UniProt protein accession: KCMB1, Q16558; KCMB2, Q9Y691; KCMB3, Q9NPA1; KCMB4, Q86W47.

Figure 3

Topological representation of human Calcium-activated potassium channel β subunits. Using Protter visualizator (Omasits et al., 2014). UniProt protein accession: (A) KCMB1: Q16558, (B) KCMB2: Q9Y691, (C) KCMB3: Q9NPA1, (D) KCMB4: Q86W47.

Figure 4

Toxin structure. (A) Charybdotoxin: PDB ID 2CRD; (Bontems et al., 1992). (B) Martentoxin: PDB ID 1M2S (Wang et al., 2005). (C) Iberiotoxin: PubChem ID 16132435. (D) Slotoxin: PubChem ID 16133816. Using PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LL. Green: carbon atoms, white: hydrogen atoms, red: oxygen atoms, blue: nitrogen atoms, yellow: sulfur atoms.

Figure 5

Sequence alignment of the ChTX family of K⁺ toxins. Using MUSCLE software (Edgar, 2004). UniProt protein accession: Charybdotoxin, P13487; Iberiotoxin, P24663; Slotoxin, P0C182; Martentoxin, Q9NBG9.

Figure 6

Chemical structure of unsaturated fatty acids that modulate BK channel activity. (A) PAM, Palmitoleic Acid; (B) OA, Oleic Acid; (C) LA, Linoleic Acid; (D) ALA, Linolenic Acid; (E) AA, Arachidonic Acid; (F) EPA, Eicosapentaenoic Acid; (G) DHA, Docosahexaenoic acid; (H) 11, 12 EET, 11, 12 Epoxyeicosatrienoic acid; (I) 14, 15 EET, 14, 15 Epoxyeicosatrienoic acid. Using PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LL. Green, carbon atoms; white, hydrogen atoms; red, oxygen atoms.

Figure 7

Chemical structure of steroids and other molecules that modulate BK channel activity. (A) 17β-Estradiol. (B) Tamoxifen. (C) Dehydroepiandrosterone. (D) Corticoesterone. (E) Lithocholic acid. (F) Dehydrosoyasaponin-I. Using PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LL. Gray, carbon atoms; white, hydrogen atoms; red, oxygen atoms; blue, nitrogen atoms.