The Large-Conductance, Calcium-Activated Potassium Channel: A Big Key Regulator of Cell Physiology

Abstract

Large-conductance Ca²⁺-activated K⁺ channels facilitate the efflux of K⁺ ions from a variety of cells and tissues following channel activation. It is now recognized that BK channels undergo a wide range of pre- and post-translational modifications that can dramatically alter their properties and function. This has downstream consequences in affecting cell and tissue excitability, and therefore, function. While finding the "silver bullet" in terms of clinical therapy has remained elusive, ongoing research is providing an impressive range of viable candidate proteins and mechanisms that associate with and modulate BK channel activity, respectively. Here, we provide the hallmarks of BK channel structure and function generally, and discuss important milestones in the efforts to further elucidate the diverse properties of BK channels in its many forms.

Keywords: BK channels; intracellular Ca2+; membrane potential; nervous system; smooth muscle.

Figure 1

Schematic diagram of the general BK channel structure. BK channels constitute tetramers of the channel pore-forming α-subunits (top). Each α (Slo1) subunit contains 3 main domains: a voltage sensor domain (VSD, S0-S4), a pore-gate domain (S5-S6) and a C-terminal cytosolic region, which functions as a Ca²⁺ sensor domain (S7-S10) (bottom). The Ca²⁺ sensor domain is constituted by two non-identical domains (i.e., RCK1 and RCK2) which contain high-affinity binding Ca²⁺ sites (Ca²⁺ bowl) and several modulatory domains for multiple ligands or cations including Mg²⁺.

Figure 2

STOC-mediated vasodilation mechanism. In vascular smooth muscle, BK channels are key drivers of negative feedback control via the regulation of membrane excitability, an essential mechanism that prevents excessive constriction of resistance arteries (1). Specifically, transient activation of ryanodine receptors (RyR) residing in the sarcoplasmic reticulum leads to the generation of “Ca²⁺ sparks” (2). Single sparks increase the Ca²⁺ concentration in the vicinity of membrane BK channels, provoking their opening and the subsequent development of macroscopic K⁺ currents referred to as “Spontaneous transient outward currents (STOCs)” (3). This in turn, contributes to membrane hyperpolarization by reducing the voltage-gated Ca²⁺ channel (VGCC) open probability (4), and a relative reduction in the intracellular Ca²⁺ levels (5). As a result, the resistance artery develops a dilatory response (6), a vital feedback mechanism to optimize arterial tone development (Nelson et al., 1995).

Figure 3

Diagrammatic summary of the pharmacology of BK channels. BK channels can be activated (i.e., opened) or blocked (i.e., closed or inhibited) leading to cell membrane hyperpolarization and depolarization, respectively. Diverse endogenous mediators, redox derivatives and, signaling proteins are able to either potentiate or inhibit BK channel activity. Numerous BK channel inhibitors/blockers have been also reported, including: toxin peptides from scorpion venoms, non-peptide alkaloids, organic amines, quinolone and imidazole derivatives. Additionally, an extensive list of cations including H⁺, Na²⁺, Cs⁺ and Ba²⁺ are shown to influence BK channel activity. Similarly, endogenous and synthetic openers have been widely studied as experimental tools and potential therapeutic approaches for different vascular or neurological disorders involving BK channels.