The BK potassium channel in the vascular smooth muscle and kidney: α- and β-subunits

review

http://www.kidney-international.org & 2010 International Society of Nephrology

The BK potassium channel in the vascular smooth muscle and kidney: a- and b-subunits Roland S. Wu1 and Steven O. Marx1,2 1

Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA and 2Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York, USA

The large-conductance voltage and calcium-sensitive BK channel is important in many electrically active cells. Its unique sensitivity to both intracellular calcium levels and membrane potential makes it a key regulator of intracellular calcium, a critical second messenger in cells. The BK channel is expressed ubiquitously in the body and has particularly significant roles in the neuronal and smooth muscle cells. More recently, the importance of BK channel in the pathophysiology of hypertension has been demonstrated. In this review, we will focus on function, regulation, and clinical significance of the BK channel. We will also specifically concentrate on one of its b-subunits, b1, which is important in vascular and renal physiology. Kidney International (2010) 78, 963–974; doi:10.1038/ki.2010.325; published online 22 September 2010 KEYWORDS: hypertension; ion channel; K channels; potassium channels; renal physiology

The BK channel (Maxi-K, Slo1, KCa1.1, Big Potassium) is a large-conductance potassium channel. It is unique among potassium channels in that it is activated, or gated, both by membrane depolarization and intracellular calcium (Ca2 þ ), making it particularly suited for intracellular Ca2 þ regulation.1 Activation of the channel leads to pore opening and outward potassium (K þ ) flux, which shifts the membrane to more negative potentials. This membrane hyperpolarization reduces activity of L-type Ca2 þ channel (LTCC) and other high-voltage-gated Ca2 þ channels. Thus, the BK channel can be viewed as a ‘thermostat’, regulating the intracellular Ca2 þ concentration. The ability of BK channel to sense both membrane depolarization and intracellular Ca2 þ allows it to integrate these signals to fine-tune the electrical activity of the cell. In humans, alterations in the BK channel are known to be important to the pathophysiology of hypertension,2–6 epilepsy,7–10 cancer,11–15 and asthma.16 This review will focus on the function and regulation of the BK channel expressed on the plasmalemma of cells with a focus on the BK channel auxiliary protein, the b1 subunit. We will also discuss clinical studies of the channel with emphasis on blood pressure and kidney function. STRUCTURE–FUNCTION BK a-subunit

Correspondence: Roland S. Wu or Steven O. Marx, Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. E-mail: [email protected] or [email protected] Received 12 May 2010; revised 7 July 2010; accepted 13 July 2010; published online 22 September 2010 Kidney International (2010) 78, 963–974

A functional BK channel is composed of a tetramer of a-subunits that form the pore of the channel. The existence of the channel was first detected in the Drosophila slowpoke mutant in the early 1980s.17 The a-subunit, encoded by the KCNMA1/Slo1 gene, was then cloned from Drosophila and mice in the early 1990s.18–20 The BK channel is expressed in a wide variety of tissues.21 It is most abundant in the brain and smooth muscle-containing organs, but has also been detected in a wide variety of other tissue types, including the reproductive organs (ovary, testes), pancreas, and adrenal glands, but, notably, not in cardiac (ventricular) myocyte plasma membranes. The ubiquitous expression of the channel is reflected by the multiple abnormalities observed in mice with targeted deletion of the BK channel gene.22–25 These mice have cerebellar dysfunction in the form of impaired motor coordination, abnormal locomotion, and abnormal eye blink 963

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RS Wu and SO Marx: The function and regulation of the BK potassium channel

C α

C Extracellular

S0

S1

S2

S3

S4

P

S5

S6

TM1

C

C TM2

Intracellular β

Ca bowl

RCK2

RCK1 90°

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S0 S1

S0

S4 P

TM2

S5

S3

S4 S6

S5

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S2 S5

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S6

TM2

P S3

S4

S4

S0

S1 S3

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αvoltage-sensing bundle

β

S2

Pore and selectivity filter

Figure 1 | The BK a- and b-subunits. Scheme representing the threading of BK a- (a) and b- (b) subunits through the membrane. (c) Proposed arrangement of a-subunit transmembrane helices at the level of the membrane, top down view. The S1–S6 helices are based on the KV1.2/KV2.1 structure.31 (Adapted from Liu et al.33).

reflex that is due, in part, to reduction of activity of cerebellar Purkinje cells.22,25 They also develop systemic hypertension caused by altered vascular tone, as determined by vessel diameter measurements of pressurized arteries, and hyperaldosteronism, perhaps resulting from loss of BK channel in the adrenal gland or impaired renal potassium handling.24,26 BK a-subunit null mice also have increased bladder contractions and urinary frequency, confirming the importance of BK channel in non-vascular smooth muscle tissues.25,27,28 Interestingly, a smooth muscle-specific inducible BK deletion model produces a more severe overactive bladder phenotype. Compensatory mechanisms such as decreased LTCC current density, increased protein kinase A (PKA) expression, and blunted response to b-adrenergic stimulation may attenuate the effects of constitutive BK deletion.29 964

The BK channel shares homology with all voltage-gated K þ channels with six transmembrane (TM) helices, S1–S6, and a pore helix (Figure 1a). The S1–S4 helices are arranged in a bundle that forms the voltage-sensing unit of the channel and the S5–S6 and pore helices form the pore and the K þ selectivity filter. The BK channel is unique among voltage-gated K þ channels, in that it contains an additional S0 helix N-terminal to S1.30 On the basis of the crystal structures of the mammalian voltage-gated K þ channel KV1.2 and a chimera of KV1.2/KV2.1,31,32 as well as disulfide crosslinking of the extracellular flanks of the TM helices,33,34 we have determined the S0 TM helix closest to S3–S4, between two neighboring a-subunits (Figure 1c). The Nterminal segment crosses over the S3–S4 extracellular loop, forming an endogenous disulfide between a Cys14 in the Kidney International (2010) 78, 963–974

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RS Wu and SO Marx: The function and regulation of the BK potassium channel

Table 1 | b-Subunit waveforms and characteristics

a

a+b1

a+b2

a+b3a

a+b4

Most abundant expression

Smooth muscle

Brain Pancreas Ovary

Brain Testes Adrenal gland

Effects on BK channel

m Apparent Ca sensitivity m Surface trafficking

Activating Rapid inactivation

Brain Pancreas Spleen Liver Perhaps activating Rapid inactivation Outward rectification

Physiologic function

Blood pressure Glomerular filtration Potassium metabolism Bladder function

Unknown

Brain function

Brain function Alcohol tolerance

Inhibits channel at low calcium Promotes channel opening at high calcium

Shown above are BK channel waveforms and characteristics.

N-terminal segment and Cys141 in the S1–S2 extracellular loop. The S0 TM helix and N-terminal segment extracellular to the S0 domain are required for the b1 subunit to modulate the channel.30,35–37 Similar to other voltage-gated K þ channels, the BK channel contains charged arginines (Arg) in the S4 domain, which collectively contribute to the gating charge (qgating). However, only one of these Arg (Arg213) together with positively charged residues in S2 (Asp153, Arg167) and S3 (Asp186) are potentially voltage sensing.38,39 Compared with other voltagegated K þ channels, the BK channel V50’s for gating charge movement (gating current) and for channel opening are shifted to much more positive voltages. Although the BK channel has a smaller gating charge, the electrostatic energy required for activating the voltage sensors is greater for the BK channel than for other voltage-gated K þ channels.38,40,41 The C-terminal tail confers the Ca2 þ -sensing ability of the BK channel, which is thought to involve two Ca2 þ -sensing domains that regulate the conductance of K þ (RCK), RCK1, and RCK2. The presence of RCK domains in the BK channel was inferred from structural data of prokaryotic Ca2 þ -gated potassium channels containing RCK domains.42,43 The second RCK domain contains a Ca2 þ bowl domain and the importance to Ca2 þ sensing has been confirmed.43–47 The recently solved crystal structure of the BK channel C terminus shows that the octamer of RCK domains in a complete BK channel forms an intracellular Ca2 þ -gating ring.48 Opening of the Ca2 þ -gating ring is thought to couple to channel opening by tugging on the pore through a spring-like S6-RCK1 linker in response to Ca2 þ .49 Correlation of this structure to mutational studies suggests that the C terminus may also have the ability to influence channel opening by modulating the voltage sensor, in addition to affecting the pore directly.48,50 Although membrane potential and Ca2 þ levels are the primary determinants of BK channel activation, other factors also influence channel opening. The BK channel Ca2 þ Kidney International (2010) 78, 963–974

sensors have high specificity for Ca2 þ over other divalent cations.51 However, magnesium (Mg2 þ ) also affects channel gating.52 Although it is ineffective at opening the BK channel, Mg2 þ enhances activation of opened channels through a distinct binding site involving the voltage sensor and RCK1 domain.44,50,53,54 Channel gating can also be affected by the redox state of the channel.55 The effects of redox modifications on the BK channel are complex, because of amino acidspecific effects of oxidation and perhaps differential b-subunit expression.56–60 Preferential oxidation of methionines generally enhances activation of the channel, whereas oxidation of cysteines generally inhibits the channel.57,58 Redox state of the channel also appears to influence BK channel interactions with other proteins, such as heme.61 BK b-SUBUNITS

The BK channel associates with modulatory b-subunits. These proteins are expressed in a cell-specific manner with each having unique regulatory effects on the channel. This fine-tuning of the channel accounts in part for the functional diversity of the BK channel. There are four distinct b-subunits, b1–4 (KCNMB1, KCNMB2, KCNMB3, and KCNMB4) (Table 1). The b1 subunit is expressed in smooth muscle and kidney, among other tissues.62–65 The b4 subunit is primarily expressed in neuronal tissue.21,66 Deletion of the BK b4 gene (KCNMB4) in mice leads to temporal lobe epilepsy and increased tolerance to alcohol, suggesting a role of the b4 subunit in alcohol sensitivity.67,68 The b2 subunit is expressed most abundantly in the brain as well as the pancreas and uterus.21,47,69 The b3 subunit is the least studied of the b-subunits. It is expressed in a wide variety of tissues, including brain.7,21,66,70 A nonsense mutation leading to a truncation of the C-terminal end of the b3 subunits in humans has been implicated in idiopathic generalized epilepsy.10 BK channel b-subunits consist of two TM domains with intracellular N and C-termini and a long extracellular loop (Figure 1b). The b-subunits are believed to co-assemble in a 965

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RS Wu and SO Marx: The function and regulation of the BK potassium channel

1:1 stoichiometry with the a-subunit.71 Disulfide crosslinking studies have shown that the extracellular flank of the first TM helix (TM1) is localized near the S1 and S2 helices of a and the second TM helix (TM2) is localized near the S0 domain of a (Figure 1c).34,72 This places the extracellular ends of the b-TM helices within the crevice formed by neighboring voltage-sensing bundles of the a-subunit.33 The b-subunit extracellular loop can confer variable resistance to toxins (for example, iberiotoxin) and the intracellular N- and C-termini can confer a variety of electrophysiologic effects.56,69,73–77 The b1 subunit was the first BK b-subunit to be cloned and is primarily expressed in smooth muscle cells.62,65,78,79 The b1 subunit alters the gating kinetics to favor a more open state and, to a lesser degree, increases Ca2 þ affinity.41,80 The result is a shift of channel activation to more negative membrane potentials. Physiologically, the b1 subunit enhances the coupling of ryanodine receptor-mediated Ca2 þ sparks to BK channel-mediated spontaneous transient outward currents. An increased frequency and amplitude of spontaneous transient outward currents lead to hyperpolarization of smooth muscle cells, and subsequent reduction of Ca2 þ influx and relaxation. b1 coexpression with a also increases surface trafficking of the a-subunit.81 Deletion of the b1 subunit in mice leads to increased arterial tone and elevated systemic blood pressure.63,82 BK channels from smooth muscle cells isolated from these mice were less responsive to Ca2 þ and had abnormal coupling of Ca2 þ sparks to spontaneous transient outward currents. Subsequent studies have also found that loss of the b1 subunit leads to impaired flow-stimulated kaliuresis resulting in hyperaldosteronism.64,83 Smooth muscle dysfunction also manifests in the bladder with decreased contraction amplitude and contraction frequency.84 Alternative splicing of the a-subunit

The BK channel is subject to extensive alternative splicing, which can have significant consequences on the function of the channel.85–89 One variant in particular, the STREX (stress axis-regulated exon) variant, has striking effects on channel function.88 This splice variant is formed by the inclusion of an exon encoding a 59 amino acid addition in the C-terminal tail of the channel. Exposure to androgens in adrenal chromaffin cells and progesterone or estrogen receptor antagonists in myometrial cells stimulates inclusion of the STREX exon.90,91 Conversely, glucocorticoids cause exclusion of the STREX exon in adrenal chromaffin cells.91 The STREX variant is a more active channel than the channels lacking the exon (ZERO variant), opening at more negative potentials.88 Regulation by kinases is also affected, as PKA activates BK channels in the absence of the STREX exon, but inhibits channels containing the STREX exon by phosphorylating an exon-specific PKA consensus site.92 The inhibitory effects of PKA phosphorylation on STREX-containing channels are blocked by glucocorticoids.93 In addition, the STREX exon alters the effects conferred by the b4 subunit.94 966

Phosphorylation

Phosphorylation is the final common pathway of many cellular signaling pathways. Adrenergic, nitric oxide, and renin-angiotensin-aldosterone systems all have important roles in biological processes and can exert their effects through phosphorylation. For all of these pathways, the BK channel represents an important phosphorylation target.95,96 Through b2-adrenergic receptor stimulation, isoproterenol activates the BK channel ZERO splice variant, both through direct stimulation by G-proteins and G-proteincoupled activation of PKA.97 Phosphorylation of all four subunits of the tetramer are required for the stimulatory effect on the ZERO splice variant, whereas phosphorylation of only one subunit of the tetramer at the STREX-specific PKA site is required to inhibit the channel.98 PKA phosphorylation requires a macromolecular signaling complex between BK channel, the b2-adrenergic receptor, and AKAP79/150.99 We also showed that BK channels and LTCC form a macromolecular complex through dimerization of the b2-adrenergic receptor.99 The PKA catalytic subunit was shown to associate with the BK channel C terminus through leucine zipper interactions,99,100 similar to the leucine zippermediated interactions found for ryanodine receptor,101 KCNQ1-KCNE1,102 and LTCC.103 The nitric oxide/cyclic guanosine monophosphate (cGMP) pathway activates the BK channel through protein kinase G.104–106 It has also been suggested that protein kinase G is the primary pathway of BK channel stimulation by both cAMP and cGMP.107 Dopamine receptor-mediated stimulation of BK channel may occur through protein kinase G, and has been shown to mediate relaxation in coronary and perhaps renal arteries.108 The effects of protein kinase C on the BK channel are less clear, likely reflecting the diversity of protein kinase C isoforms and function in different tissues. Experiments in different cell types have shown both inhibitory and stimulatory effects on BK.109–115 In addition, it has been suggested that protein kinase C phosphorylation has two roles, one mediating direct inhibition of the channel, and another as a switch to influence the effects of PKA and protein kinase G phosphorylation on the channel.116,117 BK CHANNEL IN HYPERTENSION Smooth muscle cells

BK channel function is perhaps best characterized in smooth muscle cells, which are the primary determinants of blood vessel contractility. Endothelial BK channels may also influence vascular tone by altering endothelial function, but the characterization of BK channel in these cells is still in the nascent stages.118 A variety of K þ channels in addition to BK channel are expressed in smooth muscle cells, including other voltage-gated K þ channels, inward rectifying channels, and ATP-sensitive K þ channels. However, BK channel is unique in its role in Ca2 þ handling and myocyte contraction due to its unique sensitivity to both Ca2 þ and voltage as well as its large conductance. Kidney International (2010) 78, 963–974

RS Wu and SO Marx: The function and regulation of the BK potassium channel

In arterial smooth muscle cells, membrane depolarization triggers opening of the LTCC leading to Ca2 þ influx into the cell, which along with sarcoplasmic reticulum Ca2 þ release, increases global cytoplasmic Ca2 þ , and promotes myocyte contraction (Figure 2).119 At least two channels in the sarcoplasmic reticulum participate in Ca2 þ release, the ryanodine receptor and the inositol triphosphate receptor. The inositol triphosphate receptor is more abundant than ryanodine receptor in smooth muscle cells and responds primarily to inositol triphosphate, generated from activation of G-protein-coupled receptors and phospholipase C, as well as cytoplasmic Ca2 þ and perhaps direct metabotropic stimulation from the LTCC.120,121 The ryanodine receptor participates in Ca2 þ -induced Ca2 þ release and is affected by both cytoplasmic and luminal sarcoplasmic reticulum Ca2 þ .122,123 Ca2 þ flux through ryanodine receptor is not equally distributed through the cytoplasm of the cell, with highest concentrations found within 20 nm of the channel.124,125 Thus, ryanodine receptor opening rapidly generates a large, local increase in Ca2 þ levels, a phenomenon known as a Ca2 þ spark.126 In vascular smooth muscle cells, opening of the ryanodine receptor leads to Ca2 þ -driven activation of the BK channel and resultant outward K þ flux, known as spontaneous transient outward currents.127,128 In this way, the BK channel acts similar to an endogenous Ca2 þ channel blocker counteracting the effects of the LTCC. This interplay between the BK channel, ryanodine receptor, and LTCC forms a balance that can favor contraction or relaxation depending on regulation of the system. The importance of the BK channel in vascular smooth muscle cell function was clearly demonstrated in arterial tone studies in the a- and b1-null mice. Compared with wild-type mice, cerebral arteries from b1-null mice had increased constriction, measured by vessel diameter in response to pressure.63 This difference was eliminated by applying the BK-specific blocker iberiotoxin, which had very little effect on the b1-null mice arteries. Similarly, BK a-null mice had increased tibial artery constriction measured by luminal diameter analysis compared with wild-type mice.24 The investigators also found that the BK a-null mice had impaired response to cGMP-mediated, but not adenosinemediated, vasorelaxation indicating that the BK channel is an important effector of the cGMP pathway. The b1 subunit expression is affected in disease models. b1 expression is decreased in vascular smooth muscle cells from hypertensive, diabetic, and hypoxic rodent models, likely accounting, in part, for the observed abnormalities in vascular reactivity observed in these diseases.129–132 Conversely, upregulation of b1 and enhanced coupling of Ca2 þ sparks to BK channel activation was found in a rodent model of hemorrhagic shock, suggesting that BK channels may also contribute to reduced vascular tone complicating hemorrhagic shock.133 Renin-angiotensin-aldosterone system

The BK channel and renin-angiotensin-aldosterone system are functionally intertwined. Angiotensin II has complex Kidney International (2010) 78, 963–974

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effects on the BK channel in different tissues.134,135 b1 subunit expression is reduced by angiotensin II through the calcineurin/NFATc3 pathway.136 Administration of angiotensin II to wild-type mice causes a decrease in cerebral arterial b1 subunit mRNA transcription and an increase in blood pressure. These changes are not seen in the mice with deletion of the NFATc3 gene. In a streptozocin-induced diabetic rat model, the inhibitory effect of angiotensin II on BK channel in coronary arteries is enhanced, because of the increased caveolar targeting of the channel.137 The reninangiotensin-aldosterone system also regulates a-subunit expression. Mice with constitutively overexpressed aldosterone synthase downregulate BK channel mRNA transcription and protein expression in smooth muscle cells.138 This translates into impaired relaxation of vascular rings on wire myograph. The BK channel a-subunit is expressed in the zona glomerulosa of the adrenal gland, and disruption of the BK channel in the adrenal gland is postulated to generate increased aldosterone levels accounting in part for the hypertension observed in a-subunit null mice.24 This study found increased myogenic tone in the a-null mice, suggesting that vascular dysfunction from impaired BK channel function in vascular smooth muscle cells could also contribute to the observed hypertension. Grimm et al.83 investigated whether hyperaldosteronism was also present in the b1-null mouse. b1-null mice have impaired flow-stimulated K þ secretion, leading to compensatory hyperaldosteronism and subsequent hypertension. These mice were treated with the mineralocorticoid receptor antagonist eplerenone, which reduced blood pressure by 70%. The authors concluded that the elevated blood pressure in the b1-null mouse is primarily due to hyperaldosteronism caused by defective K þ handling in the distal nephron. Human hypertension studies

Single-nucleotide polymorphisms of the b1 subunit have been correlated with both heart rate variation and baroreflex response, suggesting it is important in the physiology of blood pressure.139 The most well-studied polymorphism in humans is the b1 Glu65Lys variant.2 This Lys-substitution polymorphism of the b1 loop resulted in a small but significant activating shift of the channel’s conductance– voltage relationship compared with Glu65 in vitro. The Lys variant also conferred protection from diastolic hypertension in a subset of strictly normotensive and strictly hypertensive patients in a population-based genetic study of a Spanish cohort (REGICOR study). A separate analysis of this cohort investigated the effect of age and sex on these protective effects.3 This study found that the correlation between the Glu65Lys variant and protection from hypertension was more robust in older women, with additional association of decreased risk of the combined end point of myocardial infarction or stroke. Subsequently, an investigation of the Inter99 cohort also found Glu65Lys-associated protection from hypertension.5 This was a retrospective case–control 967

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RS Wu and SO Marx: The function and regulation of the BK potassium channel

3Na+

Ca2+

NCX

BK α/β1

LTCC

Extracellular

Intracellular

+ K+ Ca2+ Ca2+ Ca2+

Ca2+

RyR

Ca2+

Ca2+

IP3R

Ca2+

Ca2+

Ca2+

Ca2+ Ca2+

Ca2+

Ca2+

Sarcoplasmic reticulum

Ca2+

Actin-myosin

SERCA

3Na+

Ca2+

BK α/β1

LTCC

NCX Extracellular

Intracellular + Membrane potential and contractile regulation –

K+

Ca2+

Ca2+

Ca2+

RyR IP3R

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Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+

Ca2+ Ca2+

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Ca2+

Actin-myosin

SERCA 3Na+

Ca2+

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BK α/β1

LTCC –

Extracellular

Intracellular

+ K+

Ca2+

2+ Ca2+ Ca Ca2+ Ca2+

Ca2+

Ca2+

RyR

IP3R Ca2+

Ca2+ Ca2+

Ca2+ Ca2+

Actin-myosin

Ca2+

Ca2+ Ca2+

Ca2+

Ca2+ Ca2+

Sarcoplasmic reticulum

Ca2+

SERCA 2þ

Figure 2 | A model for the role of BK channel in Ca handling in vascular smooth muscle. (a) Under conditions supporting vasoconstriction, global Ca2 þ increase and sarcoplasmic reticulum (SR) calcium release driven by L-type Ca2 þ channel (LTCC) and the inositol triphosphate (IP3)/Ca2 þ /metabotropic activated release of the IP3 receptor (IP3R), respectively, promote cell contraction. (b) Under conditions supporting an intermediate level of vessel constriction, LTCC activation is balanced by BK channel activity. Global Ca2 þ levels are decreased by Na þ –Ca2 þ exchanger (NCX) extrusion and Ca2 þ –ATPase (SERCA) loading into the SR. (c) Under conditions favoring vasodilation, periplasmalemmal RyR Ca2 þ release is stimulated by SR luminal Ca2 þ levels, leading to a localized Ca2 þ spark that activates the BK channel. This leads to hyperpolarization of the membrane and inhibition of LTCC activity.

analysis of Danish patients, which found a correlation of Glu65Lys carrier status with lower systolic, diastolic, and mean arterial blood pressure. A reduction in risk of hypertension was not found in a separate study of Japanese patients.140 This study was designed to confirm 968

the effects of three previously published genetic variants associated with significant effects on hypertension, one of which was the Glu65Lys variant of BK b1. This study did not find any correlation of the variant with protection from hypertension. Authors suggested that this might be due to a Kidney International (2010) 78, 963–974

RS Wu and SO Marx: The function and regulation of the BK potassium channel

modest benefit of the variant over Glu65 or ethnicity-specific differences. The influence of BK channel genotype on sensitivity to antihypertensive medications has also been investigated. One such study involved two cohorts (Heart Score and Framingham) and correlated Glu65Lys carrier status with blood pressure.141 This study found a significant association of Glu56Lys carrier status with lower systolic and diastolic blood pressure only in the setting of antihypertensive treatment. A pooled analysis of the two populations suggested that this difference was found primarily in patients treated with b-blockers. Another study evaluated the effect of b1 variants on response to the Ca2 þ channel blocker verapamil.142 The cohort was derived from patients in the INVEST study, a prospective randomized trial comparing the effect of sustained release verapamil to atenolol on cardiovascular outcomes.143 The analysis found that in patients treated with verapamil, those carrying a Val110Leu variant were less likely to reach the primary outcome of death, myocardial infarction, or stroke than patients homozygous for the Val110 allele. A significant difference was not observed in the arm that was treated with atenolol. These investigators also did not find a significant difference in the primary end point between Glu65Lys carriers and those with the Glu65 genotype, but did find that Glu65Lys carriers treated with verapamil reached target blood pressure faster and required fewer medications. BK a-subunit variations are also important in hypertension. Another analysis of the Spanish REGICOR study investigated the BK a-subunit C864T variant and the intronic IVS17 þ 37T4C (substitution from T to C of the 37th base pair upstream of exon 17) variant in relation to hypertension.4 They found that both of these genotypes independently correlated with increased risk of hypertension and presence of both variants increased risk for myocardial infarction. It is unclear how the intronic variation alters the channel. The investigators explored the possibility of alternative splicing, but no evidence of this was found. The authors suggest that this change may alter the mRNA processing or associate with a distinct and physiologically important alteration through linkage disequilibrium. These findings further established the BK channel as an important factor in hypertension and cardiovascular risk. RENAL FUNCTION AND K þ HANDLING BK channel in the kidney

The BK channel a-subunit has been found in nearly every segment of the nephron, and all b-subunit subtypes have been found in the nephron.144–147 The role of BK channel in the kidney is complex and requires further investigation. Here, we will focus on the BK channel effects on K þ secretion and refer readers to a more comprehensive review for further details.148 The segment in which BK channel is the most studied and functionally elucidated is in the distal nephron. BK channel is localized on the apical membrane of these cells along with the Kidney International (2010) 78, 963–974

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Renal Outer Medullary K þ channels (ROMK/Kir1.1/KCNJ1/ SK, not to be confused with small calcium-activated potassium channel SK/KCa2.1-3/KCNN1-3), which underlie baseline luminal K þ secretion.149 It is here in the principal cells that BK channel likely mediates flow-stimulated kaliuresis. b1-null mice have decreased fractional excretion of K þ , decreased glomerular filtration rate, and increased excretion and fractional excretion of Na þ in response to acute volume expansion.64 As expected, studies in the a-subunit null mouse also found that K þ secretion was disrupted in response to increased flow as well as high K þ load.26 Mice lacking the ROMK channel, a mouse model for Type II Bartter syndrome, are initially hyperkalemic as newborns, but later develop hypokalemia, which is in part due to enhanced BK channel activity, perhaps in response to high flow.150 This K þ secretion is ablated in ROMK null mice by administration of BK-specific iberiotoxin suggesting that the ROMK and BK channels account for the vast majority of K þ secretion in the distal tubules. The b4 subunit is also found in the nephron, where it is expressed in the thick ascending limb, intercalated cells, and distal convoluted tubule.144 In response to a high K þ diet, b4-null mice have less urinary flow, less fractional excretion of Na þ and K þ , and increased volume and K þ retention with similar aldosterone levels compared with wild-type mice.151 In this setting, b4 null mice had larger intercalated cells, leading to a smaller luminal diameter. Findings in this model suggest that the b4 subunit reduces intercalated cell size and increases intraluminal volume in the distal tubule to accommodate higher flow rates in response to high K þ loads. The mechanism of how BK channel is activated in the kidney is still being elucidated. Detection of luminal mechanical stress on the apical membrane represents a potential mechanism for detecting flow. A candidate for mediation of this sensitivity in the cortical collecting duct is the TRPV4 channel (Figure 3).152 TRPV4 is a nonselective cation channel with Ca2 þ permeability. It can be activated by a variety of stimuli, including mechanical stress. In other tissues, TRPV4 can couple Ca2 þ entry with the BK channel to form Ca2 þ -signaling complexes conferring functional mechanosensitivity to BK.153,154 Furthermore, disruption of TRPV4 in mice leads to impaired flow-stimulated K þ excretion.155 While this is an attractive model, a role for the coupling of BK channel and TRPV4 in the process of flow-stimulated K þ secretion has not been proven. There have been conflicting reports on whether TRPV4 exists on the apical membrane of the cortical collecting duct, but the majority of findings now support the existence of apical expression.152,156–158 BK channel in distal colonic K þ secretion

BK is also important in other avenues of K þ regulation. The BK channel can be found on the apical membrane of distal colonic epithelial cells, and experiments on BK channel a-subunit null mice suggest that BK channels underlie K þ secretion in the distal colon.147,159 In rodent models, this 969

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RS Wu and SO Marx: The function and regulation of the BK potassium channel

Flow-induced shear stress

Flow-induced K+ secretion

Baseline K+ secretion

K+

K+

Ca2+

Extracellular

+

+

Intracellular TRPV4

+

BK

ROMK

2+

Ca

Ca2+

Ca2+ Ca2+ Ca2+ 2+

Ca

Apical membrane

Figure 3 | Proposed mechanism for flow-stimulated kaliuresis in the apical membrane of a cortical collecting duct principal cell. Basal secretion of K þ is predominantly mediated by Renal Outer Medullary K þ channel (ROMK), which is expressed more abundantly than the BK channel. Flow-mediated mechanical stress on the apical membrane leads to TRPV4 activation, which results in more positive membrane potentials and Ca2 þ influx, thereby activating the BK channel.

excretion is increased by aldosterone and epinephrine and may be an important source of K þ loss in diarrhea.160–162 In humans, studies suggest that BK channel-mediated distal colonic K þ secretion may be an important source of K þ loss under certain circumstances. In a study of colonic biopsies, ulcerative colitis patients demonstrated increased expression of BK channel in the colonic crypts when compared with normal controls, suggesting that upregulation of BK channel may be an important source of K þ loss in ulcerative colitis-associated diarrhea.163 In end-stage renal disease (ESRD), BK channel may be a significant source of K þ excretion. In a study comparing ESRD to normal patients, ESRD patients were found to have increased immunostaining of BK channel in colonocytes and crypt cells and threefold higher rectal K þ secretion than healthy controls.164 Overexpression of apical BK channels in the colon may also be responsible, in part, for some cases of secretory K þ loss in hemorrhagic shock.165 A case report of a chronic secretory diarrhea in an ESRD patient after an episode of hemorrhagic shock found dramatically increased BK channel staining in the colonocytes and crypt cells in comparison with those of ESRD patients. These results suggest that distal colonic secretion of K þ can be significant with upregulated BK channel expression. Elucidation of the mechanisms promoting this upregulation requires further investigation. CLINICAL TRIALS OF BK CHANNEL MODIFIERS

The road of BK channel modulators to the realm of clinical medicine has been paved with disappointment. The first and most clinically well-studied BK modulator was BMS-204352, developed by Bristol Myers Squibb. BMS-204352 was found to have neuroprotective effects in an animal model of cerebral infarct.166 In rats, cerebral vessels were occluded and BMS-204352 infused 2 h after onset of infarct significantly reduced infarct size. This compound was brought to 970

phase III trial, where the trial did not find a beneficial effect in comparison with placebo.167 Two other compounds, NS8 and TA1702, reached phase II trials, but were likely abandoned by the sponsoring companies presumably due to lack of benefit in the trial.168 A phase I trial involving gene transfer of the BK channel to treat erectile dysfunction and overactive bladder was safe, but further data have not been published.169 Other studies have found BK channel to be incidentally involved in the effects of therapeutic agents. An uncontrolled study of the cGMP-specific phosphodiesterase inhibitor sildenafil in patients with New York Heart Association Class II and III pulmonary arterial hypertension suggested that the BK channel was the primary downstream effector responsible for the vasodilatory effects in the pulmonary arteries of these patients.170 The benefit of sildenafil in patients with pulmonary hypertension has been validated.171 CONCLUSIONS

The BK channel has critical and unique roles in Ca2 þ signaling. In smooth muscle cell, the channel is centrally involved in setting the sarcolemmal membrane potential, which controls the activity of voltage-dependent Ca2 þ channels, and hence contractility. In the nephron, the channel is an important regulator of K þ handling. The b1 subunit, which is primarily expressed in smooth muscle cells, has a role in blood pressure regulation. Its importance is being increasingly recognized in the setting of hypertension and hypertensive renal disease. Clinical studies have confirmed this significance, but the understanding of how to utilize this knowledge is still in its nascent stage. Future research will focus on studying channel regulation and alterations in disease states and effective manipulation of the channel. Kidney International (2010) 78, 963–974

RS Wu and SO Marx: The function and regulation of the BK potassium channel

DISCLOSURE

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All the authors declared no competing interests. ACKNOWLEDGMENTS

RSW was supported by an NIH T32 HL07854 and a Future Leaders in CV Medical Research grant from Schering-Plough, and SOM was supported by the National Institutes of Health (NIH) research Grant awards P01 HL081172, R01 HL107335, and R01 HL68093 from National Heart, Lung and Blood Institute. We thank Xiaowei Niu for reviewing the paper and helpful discussions.

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