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BKCa channels as physiological regulators: a focused review

Authors Vetri F, Saha Roy Choudhury M, Pelligrino DA, Sundivakkam P

Received 22 July 2013

Accepted for publication 31 January 2014

Published 31 March 2014 Volume 2014:7 Pages 3—13


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 6

Francesco Vetri,1,* Moumita Saha Roy Choudhury,2 Dale A Pelligrino,1 Premanand Sundivakkam2,*

1Department of Anesthesiology, 2Department of Medicine, University of Illinois at Chicago, IL, USA

*These authors contributed equally to this work

Abstract: Large-conductance Ca2+- and voltage-gated big K+ (BKCa, MaxiK, or Slo1) channels are expressed in almost every cell of mammalian tissues and participate in a multitude of physiological processes such as vascular tone regulation, neuronal excitability, neurotransmitter release, neurovascular coupling, bladder tone regulation, urinary K+ excretion, and retinal circulation. BKCa channel is a tetramer of the pore-forming α-subunit encoded by a single gene, Slo. The BKCa-α-subunits are associated with the modulatory β-subunits, which contribute to the functional diversity of the channel. BKCa channels sense and regulate membrane voltage and intracellular Ca2+, which then modulates several cell signaling and metabolic pathways. This review focuses on the main physiologic roles of BKCa channels and the pathogenesis of diseases associated with their loss or malfunction. The mechanistic information highlighted in this review is aimed to enhance the understanding of the unique and diverse roles of BKCa channels in various physiological and pathophysiological phenomena.

Keywords: neurovascular coupling, large conductance calcium, Ca2+-activated potassium channels, BKCa channel physiology


Calcium (Ca2+)-activated potassium channels (KCa) or the channels possessing large conductance (BKCa, MaxiK, KCa1.1) are mainly characterized by a high unitary conductance of ~100–300 pS.1 Unlike other subfamilies of KV, BKCa channels are both voltage- and Ca2+-regulated potassium channels. The native BKCa channel is formed by four pore-forming subunits (α) that are encoded by the Slo1 gene.13 Splicing of the Slo1 messenger (m)RNA has been shown to contribute to differences in the regulatory properties of the channel as a result of variability in the responses to steroids and the availability of the phosphorylation sites. Furthermore, studies have demonstrated the contributory role of different splice variants between tissues in voltage sensitivity of the channels.4 Importantly, the splice variation of an α-subunit may significantly alter the localization of BKCa channels to endoplasmic reticulum.27

BKCa channels belong to the family of voltage-gated potassium channels.57 However, BKCa channels are also known to be activated solely by a stimulus-evoked increase in intracellular Ca2+ concentrations ([Ca2+]i). Interestingly, the resultant large efflux of K+ ions through the activation or opening of BKCa channels repolarizes the membrane, closes the voltage-gated calcium channels (VGCC), and reduces Ca2+ influx into the cells.812 The properties of BKCa channels therefore integrate various cellular and molecular signaling events via modulation of membrane excitability and Ca2+ homeostasis.

BKCa channels have also been outlined as negative feedback regulators of membrane potential and Ca2+ homeostasis in numerous physiological processes (Figure 1). These include modulating neurotransmitter release,8 neurovascular coupling,13 regulating vascular and respiratory tone,14,15 endocrine secretion,16,17 interspike interval and spike frequency adaptation,8 and urinary bladder tone.18 Given their relevance in essential physiological processes, these channels are encoded by a substantial number of genes in higher organisms. BKCa channels are implicated in several disease conditions including epilepsy,19 diabetes,20 Alzheimer’s disease,21 subarachnoid hemorrhage,22 neuromuscular abnormalities,23 motor impairment,24 hypertension,14,25 urinary incontinence,26 overactive urinary bladder,27,28 and noise-induced hearing loss.29 This review discusses the scientific know-how on BKCa channels serving as a key regulator in various physiologic and pathophysiologic processes.

Figure 1 Signaling pathway downstream of BKCa channels involved in the regulation of various physiological processes.
Notes: BKCa channels mediate membrane potential changes that regulate Ca2+ channels. Intracellular stores of Ca2+ released to the cytosol via the ryanodine receptor of the sarcoplasmic reticulum activate BKCa channels. An increase in the intracellular Ca2+ levels and an increase in the elimination of K+ regulate several physiological processes, including vascular tone, neurotransmission, intraocular pressure, and urinary bladder tone.
Abbreviations: BKCa, large conductance calcium-activated potassium channels; PM, plasma membrane; RyR, ryanodine receptor; IP3R, inositol 1,4,5 triphosphate receptor; SERCA, sarcoendoplasmic reticulum ATPase; SR, sarcoplasmic reticulum; NCX, sodium–calcium exchanger; TRP, transient receptor potential channel; MLCK, myosin light chain kinase.

BKCa channel structure and properties

The native BKCa channel is composed of four α- and four β-subunits, present in a 1:1 ratio (Figure 2).30,31 The α-subunit contains seven putative transmembrane-spanning α helical segments and is accountable for the ion conduction, for selectivity, and for sensing the voltage alteration.32 The cytoplasmic carboxy tail contains two intrinsic high-affinity Ca2+ binding sites and phosphorylation sites and has been implicated in the direct gating of the channel. The β-subunit is composed of two transmembrane domains with a long extracellular linker, whereas the amino- and carboxy-terminals are located in the cytoplasm. BKCa-β-subunits have been shown to influence the Ca2+ sensitivity of channel gating3336 and trafficking of channels to the plasma membrane.13,37,38 Evidence clearly shows that although BKCa channels exist in differing subunit stoichiometries, a full complement of four β1-subunits is crucial for the optimal effect of the channel.39 Differences in subunit stoichiometry, isoform expression, degree of phosphorylation, or the expression of splice variants may result in channels of varying voltage, Ca2+, and stress sensitivity and selectivity (Figure 2). Furthermore the spatial localization of BKCa channels has also been reported to influence its function within a given tissue. Interestingly, an efficient activation of BKCa channels (by locally produced Ca2+ transients or sparks) requires a close proximal arrangement between sarcoplasmic reticulum (SR) and plasma membrane (PM). It is interesting to note that this spatial arrangement is usually observed in smooth muscle and endothelial cells where the SR/endoplasmic reticulum (ER) is close to PM invaginations.40 In fact, the α-subunit of BKCa is known to contain two Caveolin (Cav) binding domains and is associated with Cav-1 and Cav-2 in endothelial cells.41 It is likely that the binding of BKCa channels to Cav-1/2 proteins or its localization in caveolae may facilitate its association with other signaling partners, either directly or indirectly, such as c-Src tyrosine kinase,42 nonselective cation channels, the Trp family of proteins,43 the G-protein-coupled receptor-mediated signaling cascade,44 and actin filaments,41,45 to mention a few.

Figure 2 Structure and regulation of BKCa channel.
Notes: Schematic diagram representing the threading of BKCa channel subunits (α and β) through the plasma membrane. Agonist-mediated stimulation leads to the activation of PKA, PKC, and PKG and to the phosphorylation of the subunits, an important mechanism through which BKCa channel modulates physiological process. Cytoplasmic C-terminal domain consists of four primary Ca2+ binding sites, called the “Ca2+ bowl”. The domains sensitive to voltage, Ca2+, and stretch are also depicted.
Abbreviations: BKCa, large conductance calcium-activated potassium channels; PKA, protein kinase A; PKG, protein kinase G; EM, extracellular side of plasma membrane; IM, intracellular side of plasma membrane; STREX, hormonal stress axis exon; PKC, protein kinase C; p, phosphate binding site.

The association of BKCa channels with specific membrane domains has also been implicated in the functional coupling of this channel to other ion channels, including nonselective cation channels, transient receptor potential and VGCC.46,47 Thus, the BKCa channel serves as a physiological regulator in association with other proteins. Proteomic analysis of BKCa channel binding partners in mouse cochlea revealed that 50% of the proteins have affiliations with K+ and Ca2+ channels, whereas almost 20% of the proteins are related to mitochondria,26 suggesting a potential role of BKCa channels in many aspects of cellular and molecular dynamics. Therefore, it is imperative to delineate the structure, localization, and function of these channels to develop new and effective treatment strategies.

BKCa channels regulation of vascular tone

Vascular tone in small arteries and arterioles is the major determinant of vascular resistance in response to several stimuli, including myogenic (pressure) components and vasoactive agents.14 Myogenic constriction is a characteristic of resistance blood vessels and plays an essential role in regulating microcirculation blood flow, providing the basal tone in resistance arteries. Increased myogenic constriction has been reported in several hypertensive models and is associated with vascular diseases.

The organs that have a higher vascular tone (eg, myocardium, skeletal muscle, skin, splanchnic circulation) exhibit large vasodilatory capacity, whereas those having relatively low vascular tone (eg, cerebral and renal circulation) have low capacity. A noticeable exception to this rule is cerebral vasospasm occurring after subarachnoid hemorrhage. The blood vessels, both arterial and venous, exhibit some degree of vascular smooth muscle contraction under basal conditions, which determines the tone, and hence the diameter, of the vessel.48 Baseline [Ca2+]i, vasoconstrictor-mediated increase in [Ca2+]i, and Ca2+ sensitivity significantly contribute to the contractile state of the blood vessel wall. These processes are orchestrated via different ion channels (K+, Cl, and nonselective cation channels), which govern the membrane potential and affect the Ca2+ influx and VGCC activity. The Ca2+ flux that activates K+ channels (mainly BKCa) indirectly hyperpolarizes the membrane, promoting the closure of VGCC. The Ca entry occurring in the vicinity of ryanodine receptors on sub-plasma membrane endoplasmic reticulum is key because the Ca2+ sparks generated by the ryanodine receptor “event” are linked to plasma membrane BKCa opening and the extrusion of K+ (Figure1). Thus, BKCa channels serve as a counter-regulatory mechanism by reverting vasoconstriction, particularly in the intense myogenic constriction of resistance vessels exposed to high intraluminal pressures.14,15 Therefore, BKCa channels are the key regulators in protecting excessive vasoconstriction through a Ca2+-dependent relaxation mechanism.

The function of BKCa channels, especially in vascular smooth muscle cells, is finely tuned by its regulatory β1-subunit through enhancing the channel for its Ca2+ sensitivity. Using BKCa-β1−/− mice49 and insulin-resistant hypertensive rat models,5052 studies have revealed an increase in arterial blood pressure and left ventricular hypertrophy. Interestingly, the lack of functional β1-subunit altered the coupling between Ca2+ signaling and membrane potential changes. Furthermore, pharmacological studies blocking BKCa channels have demonstrated an increase in the decaying conduction of a local depolarization, which basically represents the junctional and plasma membrane resistance.50 A decrease in expression of β1-subunit of the BKCa channel has also been reported in coronary artery aging in humans and rats.53,54

BKCa channels are also present in endothelial cells,14,41,5558 where they contribute to hyperpolarization,59 participate in endothelial-dependent vasodilation,60 and improve endothelial dysfunction.6163 Interestingly, studies specifically designed to target endothelial BKCa channels with luminal administration of the specific blocker iberiotoxin in arteries demonstrated the restoration of vasoconstrictor responsiveness and the normalization of the membrane potential to control levels,64 suggesting an involvement of endothelial BKCa channels in vessel reactivity. Furthermore, recent studies have shown a cholesterol-dependent activation of BKCa, suggesting the role of Cav-1 in the regulation of its activity.65 However, the exact mechanisms by which Cav-1 proteins or the caveolae invaginations may affect either the localization of BKCa channels to the plasma membrane or the downstream signaling molecules, such as nitric oxide synthase, are still not clear.

BKCa channels have also been involved in coronary artery vasodilation,6669 mainly through the endothelium-mediated stimulation-dependent responses of coronary artery smooth muscle cells (CASMCs).7074 The mediators, termed endothelium-derived hyperpolarizing factor, released from endothelial cells activate BKCa channels in CASMCs.75,76 Typically, substances that constrict coronary vessels inhibit BKCa channels in CASMCs, including angiotensin II,77,78 endothelin 1,75,79 and thromboxane A2.80 Inhibition of BKCa channels by these G-protein-coupled receptors may alter several of the downstream signaling cascade, mainly protein kinase C44, c-Src kinase,42 and so on. However, studies designed to explore the role of BKCa channels in ischemic81 and metabolic vasodilation82 showed no or little effect. Nevertheless, alterations in the activity of BKCa channels were demonstrated in several vascular pathologies, including diabetes,20,83,84 atherosclerosis and ischemia,85 hypertension,25,51,76 cardiac hypertrophy,15 and cardiomyopathy.

BKCa channels in neuronal excitability and neurotransmitter release

BKCa channels are ubiquitously expressed in the central nervous system, and their expression is highly variable within different brain regions. BKCa channels play an important role in regulating neurotransmitter release at central nervous system nerve terminals, controlling action potential duration, firing frequency, and spike frequency adaptation, resulting in fast after-hyperpolarization.8 Studies intended to explore the regional distribution and the level of expression have revealed that BKCa channels are preferentially located at the axon terminals11,86 and dendrites.87,88 In neurons, the main functions of BKCa channels are to generate the fast and prolonged after-hyperpolarization (lasting from hundreds of milliseconds to seconds) after an action potential. Prominently, the generation of after-hyperpolarization contributes significantly to the maintenance of the shape and duration of the action potential.89

BKCa channels are primarily activated in response to elevations in [Ca2+]i through the opening of voltage-dependent87 or neurotransmitter-gated90 Ca2+ channels, as well as by release of Ca2+ stores.91 The activation of BKCa channels by rise in [Ca2+]i shifts the activation voltage concentration dependently into a physiological range by limiting the depolarization-induced bursting activity. In contrast, in Purkinje cells, which lack BKCa channels, the net result is a less-negative resting membrane potential and decreased amplitude of the after-hyperpolarization.92

Several studies point to a possible functional coupling between BKCa channels and voltage-gated Ca2+ channels in the central nervous system. It is clear that in several types of neurons, BKCa channels are physically associated with voltage-gated Ca2+ channels and that this complex invariably provides a mechanism by which micromolar concentrations of [Ca2+]i (calcium sparks) are delivered to BKCa channels and tightly control their activity without affecting other Ca2+-dependent signaling processes. Moreover, the characteristics of BKCa channels are largely determined by the specific subunit of voltage-gated Ca2+ channels to which they are associated and adapt BKCa channel function to the requirement of particular neurons or neuronal subcompartments. Interestingly, blocking voltage-gated Ca2+ channels correspondingly inhibits BKCa channels, as observed in conditions in which extracellular Ca2+ was removed. In lieu of voltage-gated Ca2+ channels bound to BKCa, these channels have also shown to be operated by more distant Ca2+ sources or by a global increase in [Ca2+]i. This functionality of BKCa channels has originated the term free BKCa. Free BKCa channels are well demonstrated in chromaffin cells93,94 and in CA3 pyramidal cells,11 where submillimolar concentrations of ethylene glycol tetraacetic acid inhibit the activity of BKCa channels. The free BKCa channels are believed to serve as an emergency brake in situations where extraordinarily large Ca2+ transients lead to cellular damage or apoptosis.11

Given their role in controlling neuronal excitability, BKCa channels have been increasingly implicated in several neurological disorders, including epilepsy, cerebellar ataxia, and paroxysmal movement disorders.9597 In epilepsy, studies have indicated a missense mutation (D434G) in the α-subunit BKCa gene, which is characterized by an increase in the BKCa channel’s sensitivity to Ca2+ and increased membrane currents, resulting in a gain-of-function effect.98,99 Furthermore, this mutation, also observed in the pathophysiology of idiopathic absence epilepsy, confers specific changes in the regulatory properties of the BKCa channel subunits. However, a loss-of-function BKCa channel phenotype was demonstrated to be associated with temporal lobe epilepsy, where a polymorphism in the BKCa-β4-subunit was revealed.101 Moreover, loss-of-function BKCa channel has been implicated in tonic-clonic seizures and alcohol withdrawal seizures. Thus, both loss-of-function and gain-of-function BKCa channels might serve as molecular targets for drugs to suppress certain seizure phenotypes, including temporal lobe seizures and absence seizures, respectively.

BKCa channels in mitochondria

Channel activity similar to that of plasma membrane BKCa channels have been reported in the inner membrane of mitochondria (mitoBKCa). The mitoBKCa was initially found in the glioma cells102 and later in cardiac myocyte103 and rat brain neurons.100 Several observations confirmed the existence of BKCa channel β4-subunit in the inner membrane of neuronal mitochondria.104 The changes in the cytosolic Ca2+ concentration greatly affect neuronal cell metabolism via modulating mitochondrial response. Skalska et al105 have clearly demonstrated a Ca2+-induced dissipation of mitochondrial membrane potential, an underlying process for mitochondrial respiration, metabolism, and viability. Thus, the studies delineating the presence of mitoBKCa in neurons, its contribution to mitochondrial Ca2+ signaling, and mitochondrial membrane potential changes support the neuroprotective role of mitoBKCa in specific brain structure.

BKCa channels in neurovascular coupling

Neuronal activity is thought to communicate to arterioles in the brain to promote an adequate blood supply. This phenomenon is known as neurovascular coupling and employs multiple mechanisms, including, but not limited to, purinergic signaling, cytochrome P450 products, cyclooxygenase products, and K+. One of these mechanisms is through astrocytic Ca2+ signaling to cause local vasodilation in the activated brain area. In particular, K+ released from astrocytic end feet via BKCa channels is thought to interact with K+ inward rectifier channels on pial arteriolar smooth muscle cells, inducing hyperpolarization and relaxation.13,106

Paradoxically, this communication may cause vasoconstriction in some cases. Modest increases in Ca2+ induce dilation, whereas larger increases switch dilation to constriction.107 BKCa channels in astrocytic end feet are believed to mediate the majority of the dilation and the entire vasoconstriction, implicating local extracellular K+ as a vasoactive signal for both dilation and constriction. Therefore, BKCa channels at the astrocytic end foot are able to determine both arteriolar dilation and constriction based on the [Ca2+]i changes.

Interestingly, BKCa channel dysfunction has been recently associated with pathophysiologic changes occurring during type 1 diabetes mellitus.20 In particular, a significant decrease in the pial arteriolar dilations evoked by somatosensory activation, via sciatic nerve stimulation, was found in streptozotocin-treated diabetic rats. This depressed neurovascular coupling response is likely linked to PKC-mediated changes in BKCa and K+ inward rectifier channel activity, as normal dilating responses of pial arterioles to sciatic nerve stimulation and applications of K+-channel openers were readily restored by acute PKC inhibition. Interestingly, in a model of type 2 diabetes mellitus, whole-cell currents of BKCa channels were significantly decreased in cerebral artery smooth muscle cells, compared with control, and the sensitivities of BKCa channels to voltage, paxilline, and NS1619 were all diminished in diabetic rats.108

BKCa channels in regulating retinal circulation

Vertebrate retinas share the same fundamental neuronal organization, comprising various cell classes such as photoreceptors, bipolar cells, amacrine cells, and ganglion cells. The retina receives oxygen and nutrients diffused from the choriocapillaries to the rods, cones, and nerve layers in the inner retina. Therefore, to preserve the delicate balance between the flow of blood and the needs of the retinal nerve layers, the vasculature of the retina is designed to maximize the control of capillary perfusion.

Several lines of evidence have demonstrated the existence and functional role of BKCa channels in rod signaling.109 In addition, BKCa channels have been shown to be located at the synaptic terminal, contributing to the amplification of glutamate release at the rod photoreceptor synapse.110 The signaling of BKCa channels in the cone pathway is poorly studied compared with the rod pathways. Work by Yagi and Macleish111 has hinted at the absence of BKCa channels in the cones of the primate retina. However, blocking BKCa channels induced a reduction in light-evoked input from bipolar cells and amacrine cells to ganglions in mouse retina,112 thus suggesting a possible existence of BKCa channels in the cone pathway in rodents. Furthermore, genetic deletion of BKCa channels has been shown to affect the photoreceptor and bipolar cell responses in mouse retina.

Moreover, recent studies have shown the contributions of BKCa channels in the regulation of retinal blood flow via the action of several vasodilators in endothelium and vascular smooth muscle.113 Administration of a BKCa channel opener (BMS-191011) to male Wistar rats specifically improved retinal circulation without affecting cardiovascular functions.114 Studies in diabetic retinal models demonstrate a decreased Ca2+ sensitivity of BKCa channels and an uncoupling of BKCa channel activation from Ca2+ release in diabetic retinal vascular smooth muscle cells.115 The drastic reduction in spontaneous Ca2+ sparks results in delayed activation of BKCa channel-mediated K+ outward currents, an underlying process for arteriolar vasoconstriction, as commonly observed in retinal diseases, mainly diabetic retinopathy.115117 Hitherto, studies delineating the roles of BKCa channels in retinal circulation and physiology have been unclear. More detailed investigations are warranted to enhance the understanding of the significance of BKCa channels in retinal circulation physiology.

BKCa channels in the urinary system

Maintenance of K+ concentration within the physiological range is vital for various cellular functions, including cell volume regulation and regulation of membrane electrical properties. The kidney is the primary site where balancing K+ concentration and K+ secretion in the distal convoluted tubules of nephron is critical for determining the amount of K+ excretion. Several segments of the distal convoluted tubules of nephron have been shown to express BKCa and renal outer medullary K+ channels. Although renal outer medullary K+ channels are considered the primary channels involved in K+ secretion because of their open probability, BKCa channels are suggested to contribute to the volume regulation in the distal convoluted tubules of nephron.

BKCa channels have been reported in a variety of renal cell types, including urinary bladder smooth muscle cells,118 afferent arterioles,119 glomerular mesangial cells,120,121 and visceral epithelial cells (podocytes) in the Bowman’s capsule.3 BKCa channels have been demonstrated to be negative feedback, counteracting agonist-induced contraction, mainly in mesangial cells.120,121 BKCa channels act as a conduit of K+ secretion in the distal convoluted tubules, medullary, and cortical thick ascending limbs,122 distal connecting tubules,123 and cortical collecting ducts.124 Investigations on BKCa-β1−/−-subunit knockout models failed to demonstrate an increase in flow-mediated K+ secretion, whereas BKCa-α1−/− mice showed diminished capacity to secrete K+,125 suggesting the significance of the β1-subunit in maintaining a proper renal kaliuretic function via regulating flow-mediated K+ secretion.19,126 This may also be explained by the activation of BKCa channel activation in response to cyclic guanosine monophosphate and nitric oxide synthase through the protein kinase G (PKG) pathway. Activation of BKCa by PKG via its β1-subunit127 synergistically increases BKCa currents under conditions of increased flow via enhancing the Ca2+ sensitivity of the channel.35

In addition to mediating flow-induced K+ secretion, BKCa channels in the distal nephron have been demonstrated to respond to arginine vasopressin via the PLC/Ca2+/PKC signaling pathway. Furthermore, BKCa channels have also been shown to play a role in the renal response to aldosterone and/or a high-K+ diet. Studies using iberiotoxin, a specific BKCa channel blocker, confirmed the inhibition of renal K+ secretion associated with a high-K+ diet.128 Interestingly, a study by Najjar et al129 using the isolated, perfused cortical collecting duct from rabbits administered a high-K+ diet showed an increase in the expression of BKCa channels in the apical membrane. However, it is not clear whether an accelerated K+ secretion on high K+ diet is a result of an effect of aldosterone on BKCa channel activity or its localization to the cell membrane.

BKCa channels have also been shown to play an important role in regulating urinary bladder smooth muscle function, which is associated with urinary frequency and overactive bladder. Overactive bladder is a common pathologic condition resulting from the alteration of detrusor muscle excitability linked to several myogenic and neurological factors.130 BKCa channels are predominantly involved in the relaxation of bladder smooth muscle.131 Therefore, decreased expression of BKCa channels, mainly in the bladder outlet, may result in alteration of sensory afferent activity leading to enhanced detrusor tone during urine storage.130

Physiological regulators of BKCa channels

Studies in recent years have identified an enormous list of regulatory physiological mechanisms, which may serve as potential drug targets for interfering with BKCa channel activity. Mechanisms modulating channel function include subunit composition,132 phosphorylation,132 palmitoylation,133 and alternative splicing.134,135 However, channel function may be affected at different levels, such as protein synthesis, cellular localization, and trafficking. Furthermore, several upstream signaling molecules participating in orchestrating the above mentioned regulatory mechanisms are the object of research. In general, any mechanisms that alter the presence or function of BKCa channels in the plasma membrane may profoundly influence the magnitude of whole-cell BKCa channel currents and, consequently, cell and tissue physiology.

In addition, investigations aimed to understand the molecular aspects of BKCa channel activity have revealed various target sites of the channel protein. Several allosteric inhibitors were identified and developed to inhibit its activity and functions. Few of the inhibitors, namely, tetraethylammonium, the peptide inhibitors charybdotoxin and iberiotoxin, and the fungal alkaloids paxilline and lolitrem B are widely used in both in vitro and in vivo models. Among these, iberiotoxin is the best characterized inhibitor of BKCa channel activity.64,128,136 However, iberiotoxin was identified to have several limitations on its use in whole-animal experiments because of its low-activity against channels containing the β4-subunit,137,138 as well as its impermeable nature across the cell membrane. The membrane-permeable fungal alkaloid paxilline has become widely used as a BKCa channel inhibitor in molecular physiology because of its ability to block BKCa channels complexes with β4-subunits.139 More recently, however, another fungal alkaloid, lolitrem B, has been shown to be five times more potent at inhibiting BK channels in comparison with paxilline.140,141 Seven lolitrem compounds have also been shown to be BK channel inhibitors.142 Lolitrem B is the causative agent of ryegrass staggers, a nervous disorder of animals that graze perennial ryegrass infected with the endophytic fungi Neotyphodium lolii. Using a mouse model of ryegrass staggers, it has been shown that lolitrem B produces ataxia and tremors by inhibiting BK channels.141 In addition to lolitrem B, this endophyte-grass symbiosis also produces other structurally related lolitrem analogues in which only minor structural changes have a dramatic effect on tremorgenicity.143145


This review highlights the potential roles of BKCa channels in regulating various physiological processes. Furthermore, the functional versatility of BKCa channels conferred by the assembly of auxiliary subunits and alternative splicing of the pore-forming subunits has been addressed. The information provided in this review strongly suggests that the BKCa channel, its subunits, and its associated proteins are promising targets for the regulation of various biological and physiological processes, and hence for the treatment of several diseases. This review addressed how the understanding of BKCa channel-mediated mechanisms can be used therapeutically to treat or prevent several pathologies. More studies to understand the allosteric modulations of these channels or upstream mediators, which may result in both gain- and loss-of-function, will likely result in clinically relevant compounds. In addition, the identification of BKCa channel subunit variants and their unique contribution to physiological processes is crucial to selectively target pathophysiological cascades.


The authors report no conflicts of interest in this work.



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