BK channels are widely expressed on various types of mammalian cell membranes. In some respects, BK channels are similar to the classic voltage-gated K⁺ channels, but differ in the mechanism of their activation (Salkoff et al., 2006). The minimal functional unit of the BK channel is a tetramer consisting of four α-subunits and auxiliary β-subunits (Lu et al., 2006). The α-subunit is encoded by KCNMA1 and almost ubiquitously expressed. The α-subunit is formed by seven putative transmembrane domains (S0-S6) starting with an extracellular N-terminus and four hydrophobic regions (S7-S10) connecting with an intracellular C-terminus (Lee and Cui, 2010) (Figure 1). The BK channel voltage sensor domains (VSDs) are formed by the first four transmembrane helices (S1-S4) and sense changes in membrane potentials. Each α-subunit contains one VSD; four identical VSDs arrange counter-clockwise in a bundle and confer depolarization-dependent gating to the BK channel (Ma et al., 2006). S5 and S6, together with the intervening amino acids, form a K⁺-selective pore and selectivity filter, referred to as a pore-gate domain (PGD). S0 is a unique additional N-terminal transmembrane segment serving as a site of coupling with β-subunits; this functional interaction is responsible for modulating the balance between resting and active states of the VSD (Koval et al., 2007). The C-terminal region contains four helices (S7-S10) and makes up nearly two-thirds of the total length of the primary amino acid sequence. S9 and S10 are the most highly conversed among species and can be expressed as a separate domain. The cytosolic domain is comprised of two tandem structurally homologous but non-identical regulators of K⁺ conductance domains: RCK1 and RCK2 (Yusifov et al., 2010). Each RCK domain has its own high-affinity Ca²⁺ sensing site. One is located in the RCK1 domain and includes the residue D367. The other is located in the RCK2 domain and functions as the high-affinity Ca²⁺ binding sites (Ca²⁺ bowl) (Yuan et al., 2010).

The β-subunits can be classified into four subtypes (β1-4) that are encoded by genes KCNMB1-4 respectively. The β-subunits are composed of two transmembrane helices, TM1 and TM2, with a large extracellular loop between them. TM1 lies close to S1 and S2, while TM2 is close to S0 (Liu et al., 2008). The β-subunits can alter the voltage and Ca²⁺ sensitivity of the α-subunits and regulate the kinetics and pharmacological properties of BK channels (Behrens et al., 2000). Recently, the four γ-subunits (γ1-4) of BK channels have been discovered and each contains a single-transmembrane domain. All four γ-subunits increase the voltage sensitivity of the BK α-subunit in the absence of Ca²⁺ (Li and Yan, 2016).

BK channels link chemical and electrical signaling through Ca²⁺-dependent voltage-operated activation (Pantazis and Olcese, 2016). Moreover, a wide range of intracellular ligands enable BK channels to be gated or modified (Piskorowski and Aldrich, 2006). BK channels are known to be widely distributed not only in the plasmalemma but also in the inner mitochondrial membrane and other organelles (Balderas et al., 2015) and exhibit different electrophysiological properties (Chen et al., 2005). BK channels seem to be critical regulators of vital physical functions such as blood flow, neurotransmission, urination and immunity.

In vascular smooth muscle cells, BK channels act as regulators of membrane potential and smooth muscle tone (Wang et al., 2012). With regards to their physiological activity, BK channels are viewed as negative-feedback regulators of electrical excitation (Sausbier et al., 2005). In neuronal cells, BK channels regulate brain physiology (Grunnet and Kaufmann, 2004), including shaping action potentials (Gorini et al., 2010), monitoring neurotransmitter homeostasis and signaling, and neurovascular coupling for the maintenance of vascular tone (Singh et al., 2016). In skeletal muscles, BK channels participate in modulating transmitter release by repolarization of the action potential (Maqoud et al., 2017). Tricarico et al. (2005) found that BK channels are involved in the Ca²⁺-dependent phenotype transition of the fibers, which contributes to the skeletal muscle fatigue. In renal tissue, BK channels are expressed in various kinds of renal tubular segments including distal convoluted tubule (Belfodil et al., 2003), connecting tubule (Frindt and Palmer, 2004), and cortical collecting duct. Woda et al. (2003) proposed that BK channels are involved in the regulation of K⁺ balance in the distal nephron and the cortical collecting duct. Moreover, BK channels are involved in other various body functions, including regulating circadian rhythm regulation (Whitt et al., 2016), urinary bladder function (Meredith et al., 2004), susceptibility to hearing damage (Pyott et al., 2007) and erectile dysfunction (Werner et al., 2005).

RAAS also referred to as the renin-angiotensin system (RAS), is a crucial hormone system that contributes to maintaining water-electrolyte balance and regulating arterial blood pressure. BK channels are known to associate with several RAAS factors, with each of these interactions having distinct physiological consequences. The interaction between BK channels and RAAS is emerging as a key regulator of BK channel function in both health and disease.

Renin, a protein and enzyme generated from cells in the kidney, plays a critical role in RAAS. It can cleave and activate another circulating protein, angiotensin, which represents the beginning of a chain reaction involving RAAS.

Ang II, an octapeptide hormone, plays a major role in regulating the body's blood pressure and maintaining water-electrolyte balance through sympathetic nervous activity, aldosterone-regulated sodium excretion, and thirst responses (King et al., 2013). Ang II contains two types of high-affinity plasma membrane receptors, AT1R and AT2R, and each binding respectively brings about a serious of physical effects (Carey et al., 2000). Ang II-activated receptors generate and convert downstream signals to multiple intricate reactions.

Aldosterone, the main mineralocorticoid hormone, is involved in regulating sodium and potassium homeostasis and body fluid equilibrium by means of influencing the re-absorption of Na⁺ and excretion of K⁺ in the kidney (Balakumar et al., 2017). Aldosterone is traditionally thought to play a key role in regulating salt re-absorption and potassium secretion in response to two apparently opposite conditions: hypovolemia and hyperkalemia (Ruilope and Tamargo, 2017). With regards to the decrease in blood volume, aldosterone is released and causes Na⁺ retention via salt transport mechanisms in the distal nephron, while K⁺ secretion remains unchanged. In other words, water and sodium are retained without losing K⁺. With regards to the increase of plasma K⁺, aldosterone is also activated and promotes K⁺ secretion in the distal nephron, while salt re-absorption remains unchanged. This contradictory phenomenon is referred to as the aldosterone paradox (Ming, 2011). In both hypovolemia and hyperkalemia, aldosterone causes two distinct physiological effects in order to maintain the salt and K⁺ balance, which indicates that aldosterone-mediated regulation is dependent on multiple mechanisms (Arroyo et al., 2011).

AT2 receptors are highly expressed in fetal tissues and decreases rapidly after birth. They are much less abundant in adults and are found to be expressed in the pancreas, heart, kidney, adrenals, brain, and vasculature. The AT2R is a seven transmembrane G protein-coupled receptor and has 30% similarity with the AT1R. AT2R contributes to the regulation of renal, central nervous system and cardiovascular functions (De Gasparo et al., 2000). An increasing number of fundamental experiments indicate that AT2R may suppress AT1R-mediated biological effects due to triggering of activation of apoptosis via various signaling processes. Arima et al. (1997) reported that the activation of the AT2R may lead to endothelium-dependent vasodilation through a cytochrome P-450 pathway, which in turn opposes vasoconstriction induced by the AT1R in the rabbit glomerular afferent arteriole. Dimitropoulou et al. (2001) also demonstrated that the AT2R is able to enhance Ang II-induced endothelium-dependent vasodilation by stimulating BK channels in smooth muscle. The detailed mechanisms are still unknown and are expected to be further studied.

Arroyo et al. (2011) proposed that Ang II plays a significant role in the distinct effects of aldosterone in hypovolemia and hyperkalemia, a process that involves WNK4 (Verissimo and Jordan, 2001). The WNK (with-no-lysine kinases) family is a serine/threonine kinase subfamily composed of four members known as WNK1 to WNK4, respectively encoded by genes WNK1-4. WNK1, WNK3, and WNK4 are primarily expressed in the kidney (Wilson et al., 2001). There is growing evidence that WNK4 functions as the “molecular switch” that alternates between different functional states to regulate Na⁺ and K⁺ transport in the distal nephron via mediating the activity of the Na⁺-Cl⁻ cotransporter (NCC) (Arroyo et al., 2011). Under conditions of hypovolemia (high Ang II and aldosterone levels), WNK4 demonstrates antagonistic effects of K⁺ secretion in the renal distal nephron.

The mechanisms underlying WNK4-induced inhibition of BK channels by down-regulating their expression are still not fully understood, and several different hypotheses have been put forward. Zhuang et al. (2011) proposed that WNK4 kinase is involved in K⁺ secretion in the renal distal nephron and inhibits BK channel activity dependent on its kinase activity. The inhibition likely results from lysosomal degradation instead of clathrin-mediated endocytosis of BK channels. Yue et al. (2013) drew a similar conclusion, proposing that WNK4-mediated inhibition of BK channels is due to the activation of ERK and p38 mitogen-activated protein kinase (MAPK) via a mechanism other than the enhancement of endocytosis in the cortical collecting duct. Wang et al. (2013) suggested that WNK4 or a WNK4 mutant with a region containing a coiled coil domain and a autoinhibitory domain may decrease BK α-subunit plasma membrane expression as well as the whole cell expression, which suggests that WNK4 inhibits BK channel function by enhancing the degradation of BK channels via an ubiquitin-dependent pathway in the distal nephron.

Diets rich in potassium can result in an increase in plasma potassium and promote the release of aldosterone. An increasing number of experiments have shown that, in condition of hyperkalemia, apical membrane expression of BK channels in the cortical collecting duct (CCD) is apparently elevated, which enhances K⁺ secretion and maintains K⁺ homeostasis (Najjar et al., 2005). However, there is considerable controversy on the issue as to whether or not the enhancement of BK channel activity is directly dependent on the high level of plasma aldosterone.

Some investigators hold the view that the increase in aldosterone may enhance the activity of BK channels under conditions of high dietary potassium intake. Cornelius et al. (2015) tend towards this view and demonstrated that high aldosterone concentration in low Na⁺, high K⁺ diet mice contributes to a high rate of BK channel-mediated potassium secretion, which leads to an osmotic diuresis. The high urinary flow created by BK-mediated K⁺ secretion may be activated in a positive feedback manner, indicating that BK channels may present a therapeutic target for treating hyperkalemia.

In contrast, some studies deem that aldosterone has little or no influence on the expression or the activity of BK channels in response to dietary potassium intake. Estilo et al. (2008) hold the similar view that renal K⁺ excretion is associated with a kaliuretic pathway, rather than aldosterone directly affecting renal potassium ion transport due to changes in plasma potassium concentration. Recent studies have revealed a new understanding of the major role of BK channels activated by aldosterone-independent kaliuretic factors in which BK channel expression levels are closely related with flow-stimulated K⁺ secretion (Woda et al., 2001; Welling, 2013). In the distal nephron, renal K⁺ excretion is deemed to be dependent on tubular flow rate and BK channels are activated by an increase in the tubular flow rate (Woda et al., 2003). Liu et al. (2007) proposed that flow-stimulated BK channel-mediated potassium secretion is related to a signal pathway that involves an increase in Ca²⁺ concentration, which enables BK channels to translocate from the cell to the apical membrane. Through further studies, they found that PKA and PKC are involved in regulating the activity of BK channels in the mammalian distal nephron (Liu et al., 2009).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.