Abstract
Coded by a single gene (Slo1, KCM) and activated by depolarizing potentials and by a rise in intracellular Ca2+ concentration, the large conductance voltage- and Ca2+-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 Ca2+-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 Ca2+ 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.
Highlights
Consisting of 5 families and more than 70 different encoding genes in mammals, the diversity of K+ channels is amazingly large
CONCLUDING REMARKS BK channels are related to different pathophysiological processes, such as changes in vascular tone regulation, diabetes, kidney, and nervous system diseases
The expression of auxiliary β subunits plays an important role in these processes because of the modulatory effects of these subunits on BK channel activity, inducing changes in their biophysical properties
Summary
Consisting of 5 families and more than 70 different encoding genes in mammals, the diversity of K+ channels is amazingly large (for a comprehensive review on K+ channels, see González et al, 2012). BK channels are encoded by a single gene (Slo1) They contain seven transmembrane domains and, the N-terminus is in contact with the cell external milieu (Meera et al, 1997) (Figure 1). The BK channel in mammals is ubiquitously distributed in different tissues and, because it is activated by voltage and Ca2+, it is the perfect molecular machine to reduce or stop excitatory stimuli. In vascular smooth muscle cells, BK channels regulate contractile tone. In this case, increments in local Ca2+ (i.e., Ca2+ sparks) produce BK channel-mediated spontaneous transient outward currents (STOCs), hyperpolarizing the membrane and producing muscle relaxation (Jaggar et al, 2000; Ledoux et al, 2006). The main goal of the present review is to provide an overview of our current knowledge of how such mediation and modulation are accomplished
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