BK channels in the kidney: role in K secretion and localization of molecular c - 《American Journal of Physiology》美国生理学杂志干细胞之家



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发表于 2009-4-22 08:37 |只看该作者 |倒序浏览 |打印

作者：Jennifer L. Pluznick and Steven C. Sansom作者单位：1 Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut; and 2 Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska


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      【摘要】! A1 l) n, e, u# F4 T
   Although it is generally accepted that ROMK is the K secretory channel in the mammalian distal nephron, recent in vitro and in vivo studies have provided evidence that large-conductance Ca 2  -activated K channels (BK, or maxi K) also secrete K in renal tubules. This review assesses the current evidence relating BK channels with K secretion. We shall consider the component proteins of the BK channel, their localization with respect to segment and cell type, and the electrophysiological forces involved in K secretion. Although the majority of studies have focused on a role for BK channels in flow-mediated K secretion, this review also considers a potential role for BK channels in high-K diet-induced K secretion. The division of workload between ROMK and BK is discussed as a mechanism for ensuring a constant plasma K concentration.
      【关键词】 maxi K distal nephron potassium secretion connecting tubule BK
   MAINTAINING PLASMA K concentration ([K ]) within narrow limits is necessary for a variety of cell functions, including cell volume regulation and regulation of the electrical properties of both excitable and nonexcitable tissues. The kidney is the primary site for regulating external K balance, and K secretion in the distal nephron is the critical step for establishing the quantity of renal K excretion. Although both renal outer medullary K channel (ROMK) and large-conductance, Ca 2  -activated K (BK) channels are present along several segments of the distal nephron, it has been widely accepted that ROMK channels in the cortical collecting duct (CCD) are primarily responsible for renal K secretion. In this review, we will discuss recent evidence that has warranted reconsideration of the potential contribution of BK channels, as well as of the location of K secretion.# n) V& k- t/ f3 Q

ROMK AND BK CHANNELS IN THE KIDNEY1 q" j* c- L+ L/ h* R
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Because ROMK (Kir 1.1; secretory K  , small K  , or SK channel) and BK channels comprise the two main K conductances observed in the apical membrane of the distal nephron, both are candidates for playing a role in K secretion. The role of each channel can be determined both qualitatively (regulatory and biophysical properties of the channel) and quantitatively (number of channels in the membrane), with the latter assessment being much more difficult than the former.
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Qualitative Properties of Renal ROMK and BK Channels
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ROMK channels, found in the thick ascending limb (TAL), distal convoluted tubule (DCT), connecting tubule (CNT), CCD, and outer medullary collecting ducts ( 98 ), are activated by external [K ] ( 80 ), phosphatidylinositol 4,5- bis phosphate ( 31, 46 ), and PKA ( 10, 46, 88 ) and inhibited by intracellular Ca 2  and low pH ( 80, 106 ). ROMK localization is regulated by protein tyrosine kinase and protein tyrosine phosphatase ( 44, 59 ), and membrane expression of ROMK is inhibited by both WNK3 and WNK4 ( 34, 42 ). In the CCD, ROMK forms a 30-pS channel; however, in the TAL, ROMK is also a component of a 70-pS channel that recycles K entering the cell via the Na -K -2Cl - transporter ( 49 ). With loss of ROMK function, the Na -K -2Cl - transporter is unable to function at its normal capacity and salt and water reabsorption are greatly reduced, resulting in a genetic disease known as Bartter's syndrome ( 50 ).

In the TAL, ROMK is sharply (and nearly exclusively) expressed on the apical membrane when localized by immunohistochemistry ( 40, 114 ). In the CCD and outer medullary collecting ducts, however, apical ROMK expression is much weaker, and much of the ROMK protein appears to be localized predominately in the cytosol with minor expression in the apical membrane ( 44, 98 ). When animals are given a normal- or high-K diet, ROMK localization to the apical membrane is increased in the distal nephron (beyond the TAL) compared with animals given a low-K diet ( 11, 44 ). Although both ROMK and BK are expressed in the distal nephron, most studies have concluded that ROMK channels are responsible for the majority of K secretion because they have a much higher open probability ( P o ) than BK at resting membrane potential and basal intracellular Ca 2  concentration ([Ca 2  ] i 0.8 vs. 9 b$ e6 r$ s& I5 k% k
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BK channels are large-conductance channels ( 150-250 pS) that are sensitive to changes in both voltage and intracellular Ca 2 . BK channels have been reported in a variety of renal cell types, including those of the renal vasculature such as afferent arterioles ( 14 ). Although it is believed that the role of BK channels in the vasculature is to oppose constriction, this role is relatively minor in renal afferent arterioles ( 14 ). BK channels are also present in glomerular mesangial cells ( 51, 94, 96 ), where, in contrast to afferent arterioles, they play a prominent (feedback) role in opposing agonist-induced contraction. This feedback role appears to require regulation by the cGMP-PKG pathway ( 41, 84, 95 ). Mesangial BK channels also are regulated by Ca 2  /calmodulin-dependent kinase II ( 82 ) and protein phosphatase 2A ( 85 ).! l) h$ K, ?& q9 q
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In mammalian renal tubules, evidence for BK channels has been reported in the medullary and cortical thick ascending limbs ( 27, 58, 101 ), the DCT ( 5 ), the CNT ( 17 ), the principal cells (PC) and intercalated cells (IC) of the CCD ( 33, 70 ), and the medullary collecting ducts ( 60 ). Some ( 29, 37 ), but not all ( 60 ), groups have reported BK channels in the proximal tubule. Interestingly, BK channels in the kidney tubule are activated by membrane stretch ( 101 ). It has been proposed that in the TAL ( 27, 101 ), DCT ( 5 ), CNT ( 17 ), and CCD ( 97 ), BK channels function as either volume-regulatory channels or as a pathway for K secretion. It was originally suggested that volume regulation was the primary function of BK channels in the distal nephron. However, a transport function for BK channels became evident in a micropuncture study in which the DCT/CNT was perfused. It was shown that blocking Na absorption with amiloride caused the transepithelial potential to shift in a positive direction in the presence, but not the absence, of Ca 2  ( 66 ). This Ca 2  -sensitive, positive cell-to-lumen current in high-flow conditions was consistent with the activation of a Ca 2  -sensitive K channel in the apical membrane of the distal nephron/CNT.1 r- m  N9 Y0 i- v

Quantitative Analysis of Renal ROMK and BK Channels- s3 u$ |0 W9 s/ k! r

Despite substantial progress in immunological and patch-clamp methods, it has been very difficult to determine the number of ROMK and BK channels that contribute to physiological K secretion in renal cell membranes. Antibodies and immunological approaches are excellent tools for localizing channel proteins. However, these approaches are far too dependent on technical variations to be quantitative, and they do not provide evidence on the functional state of the channels.

A recent study quantified the density of ROMK channels in CCD cells by counting single-channel currents in cell-attached patches ( 22 ). Knowing the diameter of the patch pipette, and with ROMK having a high and constant P o, these investigators calculated that the density of ROMK channels could account for the K conductance in the CCD measured with microelectrodes in other studies. However, it has not been determined whether ROMK can account for the much greater macroscopic K conductance in the CNT, where flow and the K secretory capacity is three to four times greater than in the CCD.

Indeed, the patch-clamp technique is a powerful tool for determining single-channel properties for many ion channels, and if the channels have a constant P o (e.g. ROMK), it may be useful for determining the contribution of a channel to macroscopic membrane conductance and K transport. However, the usefulness of the patch-clamp method for quantifying the physiological role of a channel with a variable P o, such as BK, may be limited. It is difficult to know the P o of BK channels in vivo under any given condition because the BK channel is particularly sensitive to factors that cannot be replicated in an experimental situation. For example, BK respond to changes in intracellular Ca 2  as well as the shear stress that accompanies laminar flow. However, to gain access to single-channel currents in renal tubules, the segment is split open, drastically altering laminar flow, and the cytoskeletal tension is altered considerably by pipette suction ( 89 ). Splitting open the tubule may release a variety of cytokines and locally acting messengers that a channel would not ordinarily be exposed to. In addition, depending on the amount of membrane present in the pipette, the surface area of the patch will vary considerably and the cytoskeletal anchoring and local Ca 2  concentrations may also be altered. This is particularly problematic for a Ca 2  -sensitive K channel. Moreover, quantifying channels in a cell membrane by patch frequency biases the results to channels that are more accessible to the pipette. Channels that are localized in or near the lateral membranes may be less frequently observed. Thus, while the patch-clamp technique can be a useful tool for identifying and quantifying certain channels in the renal tubule, the contribution of any channel (particularly BK) to the normal physiology of the cell can only be verified by in vivo experiments.6 G: I, [7 `* o
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FLOW-MEDIATED K SECRETION
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Increases in distal tubule fluid flow result in increases in K secretion ( 52, 100, 102, 111, 112 ). Flow-mediated K secretion has been carefully investigated using micropuncture techniques ( 52 ), and it has been shown that this phenomenon is attenuated in rats fed a low-K diet and is blocked by amiloride at low, but not high, flow rates. Although the "high" flow rates at which K secretion persisted in the presence of amiloride were near the upper limits of physiological rates ( 30, 52 ), they are within the range obtained with diuretic therapy ( 30, 103 ).

In fact, an important aspect of flow-mediated K secretion is the K loss caused by loop diuretics, such as furosemide. These diuretic agents are often used in the treatment of hypertension and heart failure and cause increased flow in the distal nephron, which leads to increased K secretion. Because this kaliuresis is in response to pharmacologically increased distal flow and not increased filtration rates, the loss of K is exaggerated. Consequently, low plasma K levels may be observed in patients receiving furosemide therapy ( 3, 23 ). A similar phenomenon arises in type II Bartter's syndrome, which occurs when ROMK is defective, thereby compromising K recycling in the TAL (Bartter's syndrome type I and III-VI result from mutations in proteins other than ROMK). As a result, the activity of the Na -K -2Cl - transporter is diminished and the concentrating mechanism is impaired, owing to diminished solute transport in the TAL. In the absence of medullary hypertonicity, water reabsorption is greatly reduced, resulting in increased flow through the nephron segments distal to the TAL. This increased flow stimulates K secretion in the distal nephron, sustaining kaliuresis and low plasma levels of K  . However, the K loss in type II Bartter's is not as severe as in furosemide therapy because K can still be reabsorbed in the TAL in ROMK -/-.
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BK CHANNELS IN FLOW-MEDIATED K SECRETION: EVIDENCE FROM "KNOCKOUT" MICE' N0 k! E# L  t

Recently, microperfusion of both isolated CNTs ( 102 ) and CCDs ( 110 ) from wild-type animals demonstrated a flow-dependent component of K secretion that can be blocked by pharmacological blockers of BK channels. However, the function of BK channels in flow-mediated K secretion is best illustrated in vivo by studies of mice null for the molecular components of either ROMK or BK channels. Although it is still unclear whether ROMK has associated accessory proteins, it is well established that BK channels are composed of pore-forming BK- subunits as well as accessory BK- subunits. The BK- subunits are spliced at several sites, introducing channel variability. Additional variability is provided by each of the four known -subunits, which are expressed in a tissue-specific pattern to fine-tune the properties of BK- in different ways. Although BK- subunits alone form a functional channel ( 9 ), the accessory BK- subunits are known to modulate the native Ca 2  and voltage sensitivities of BK-, as well as alter the kinase and pharmacological sensitivity of the channel ( 8, 9, 41, 56 ). Thus, the tissue-specific expression of BK- subunits serves to tailor the function of BK- as most appropriate for a given tissue.
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In the last few years, renal function of ROMK -/-, BK- -/-, and BK- 1 -/- mice has been studied, yielding insight into the role of these channels in renal K secretion. Although ROMK -/- mice no longer express the "secretory potassium" (SK, or ROMK) channel on the apical membrane of the distal nephron, their fractional excretion of K (FE K ) is increased compared with wild-type controls ( 48, 50 ). That the FE K 150% indicated that K excretion was due to secretion ( 48 ) by another K channel in the distal nephron. Although it has been proposed that ROMK is solely responsible for K secretion in the distal nephron, this example illustrates a paradox: if ROMK is defective, then what is the route for K secretion? It has therefore been suggested that another K channel in the distal nephron, BK, plays a role ( 110 ). It is believed that BK channels in ROMK -/- (type II Bartter's syndrome) are activated by increased flow due to an impaired concentrating mechanism. Indeed, it was recently found that distal K secretion in ROMK -/- mice was blocked by iberiotoxin (IBTX), a BK channel blocker ( 4 ).. Y' Z% {" |' l2 P2 W

Data from BK subunit knockouts have also provided evidence for a role of BK in flow-mediated K secretion, because mice lacking the 1-subunit of the BK channel fail to elevate K secretion (measured as FE K, %) in response to increased flow rates induced by volume expansion ( Fig. 1 ) ( 73, 74 ). These data imply that the 1-subunit of the BK channel is necessary for a proper renal kaliuretic response to increased distal flow. Importantly, a recent study examining K secretion in BK- -/- also found a diminished capacity to secrete K in response to flow ( 77 ). Therefore, it appears safe to conclude that the BK- 1-channel is necessary for proper flow-mediated K secretion.. e7 A! x, N) [) O4 ~

Fig. 1. Data relating K excretion (U K V) and flow rate in both wild-type ( ) and BK- 1 -/- ( ) mice. Individual data points from each mouse were plotted, and regression lines were drawn. A significant correlation was found in BK- 1  /  but not BK- 1 -/- mice. From Ref. 74.
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LOCALIZATION OF BK MOLECULAR COMPONENTS
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The distal portions of the nephron can be divided into the DCT, the CNT, the initial collecting tubule (ICT), and the CCD. The ICT is the initial segment of the CCD positioned before the first confluence with another tubule ( 2 ). The CNT is composed of two main cell types, CNT cells (akin to PC), and IC (subtype-A or subtype-B). The ICT and CCD are composed of PC and IC. Although IC are commonly associated with the CCD, the appearance of IC actually begins in the latter part of the DCT (distal 80%) ( 6 ) and continues throughout the medullary collecting ducts.- {) E+ F* S: I; G) A

Functional BK channels (necessarily indicating the presence of BK- ) have been reported in both the renal vasculature and the great majority of tubule segments. It appears, then, that BK- is expressed in a wide array of renal structures. However, what of the BK- subunits?+ s; r1 S4 w' ]4 m

Localization of the BK- 1
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BK channels may be composed of the -subunit alone, or together with any one of the four -subunits, raising the question of which BK subunits are involved in K secretion in the distal nephron. When the renal response to volume expansion in BK- 1 -/- mice was investigated ( 9, 73, 74 ), it was found that BK- 1 -/- mice were unable to elevate K secretion in response to changes in urinary flow rate. This effect was independent of the glomerular filtration rate because FE K in response to flow was also eliminated in BK- 1 -/- mice. This result implied that the BK- 1 subunit is present in the distal nephron and is a necessary component of the kaliuretic response to increased flow. This in vivo result prompted further investigation of the precise location of BK- 1 within the distal nephron.
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In the ensuing studies, it was found that BK- 1 expression was found exclusively in the connecting tubule ( 74 ) ( Fig. 2 ). The strict localization of BK- 1 to the CNT implies that non-CNT segments should be unaffected by the absence of BK- 1. Therefore, the localization of BK- 1 to the CNT confirms that the attenuated FE K response is truly due to a K secretion defect. Further confirmation of the localization of the BK- 1 to the CNT was provided by obtaining the sequence for BK- 1 from microdissected rabbit CNTs using RT-PCR. Although BK- 1 is expressed in the CNT of both the mouse and rabbit, only in the mouse was BK- 1 expression restricted to the CNT. In the rabbit, BK- 1 is primarily expressed in the CNT but also in a non-CNT segment, likely in a portion of the CCD or ICT ( 74 ). The functional significance of the species difference in BK- 1 expression is not known. However, the presence of BK- 1 in a portion of the rabbit CCD (presumably the ICT or early CCD) is consistent with several studies showing flow-induced K secretion in rabbit CCD ( 110, 111 ).6 x  b; l7 p) l: n
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Fig. 2. Microphotograph demonstrating immunohistochemical localization of BK- 1 to the connecting tubule (CNT; A ) and graphs summarizing the extent of colocalization of BK- 1 with various markers of distal nephron segments ( B - D ). A : Na /Ca 2  exchanger [NCX; brown, basolateral marker of late distal convoluted tubule (DCT) and CNT] and BK- 1 (red, apical) colocalize in mouse kidney. B : minimal colocalization of BK- 1 with the DCT marker, NaCl cotransporter (NCC; gray bar). C : high incidence of colocalization of BK- 1 with NCX and rare expression of BK- 1 in a tubule where NCX is not detectable (filled bar). The fraction of NCX expressed without BK- 1 (open bar) likely represents NCX expression in the late DCT. D : rare colocalization of BK- 1 with aquaporin-3 (AQP3), a marker of principal cells (PC) in the cortical collecting duct (CCD). From Ref. 74.
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It has been reported that in the CCD, the expression of BK channels in IC is higher than in PC ( 70, 111 ); however, others have found comparable expression of BK channels in these two cell types ( 43 ). Although IC may have abundant expression of the BK- subunit, our results indicate that BK- 1 is not expressed in IC. By doublestaining for BK- 1 and either H -ATPase or peanut lectin (IC markers), we have found that BK- 1 staining occurs only in non-IC ( 24 ). These data (together with the in vivo evidence from BK- 1 -/- ) suggest that flow-mediated K secretion is localized to "connecting tubule cells" ("principal cells" of the CNT) and that BK- 1 channels are primarily responsible for this phenomenon. The drastic reduction of flow-mediated K secretion in BK- 1 -/- and the absence of 1 staining in the murine CCD or in IC strongly imply that the BK channel of the CNT cells mediates flow-inducted K secretion.+ v$ L1 G: g2 ]; P

Localization of BK- 2, BK- 3, and BK- 42 ~+ z* s) y! C5 ^( Q
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Limited information is available on the localization of the other three -subunits along the nephron. To our knowledge, only one study ( 65 ) has screened for the presence of BK- subunits in a specific tubule segment. This study demonstrated that BK- 2, BK- 3, and BK- 4 (but not BK- 1) can be detected by PCR in the CCD. The absence of BK- 1 in the CCD is consistent with data localizing BK- 1 to the CNT but not the CCD ( 74 ). In addition, recent immunohistochemical evidence from our laboratory indicates that BK- 4 is expressed in ICs but not PC or CNT cells (Grimm PR, Foutz R, and Sansom SC, unpublished observations).
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The absence of BK- 1 ( 24 ) and the presence of BK- 4 in IC argues against a role for K secretion by BK channels in IC. Without BK- 1, the activity of the BK channel is dampened; in fact, the channel is no longer responsive to PKG and is much less sensitive to intracellular Ca 2 . As shown in Fig. 3, when BK- 4 is associated with BK-, BK channel activity would be reduced even further: it would be even less sensitive to changes in intracellular Ca 2  ( 9 ), and still insensitive to PKG ( 41 ). These characteristics make it unlikely that BK- or BK- 4 channels (that is, BK channels in IC) would contribute to K secretion.4 }. d6 I% e9 b' i8 I5 }3 W: ]) f$ q
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Fig. 3. Conductance ( G / G max )-voltage relationships of heterologously expressed BK- / 1 (0.8 µM Ca), BK- (1 µM Ca), and BK- / 4 (1 µM Ca). Data were replotted from studies by Dworetzky et al. ( 12 ) and Weiger et al. ( 107 ). The half-activation potentials ( V 0.5 ) were -30 mV for BK- / 1, 60 mV for BK-, and 120 mV for BK- / 4. BK channels composed of BK- / 1 in CNT cells will activate at 150 mV more negative potentials than BK- / 4 channels in IC ( 12 ).

In summary, BK- 1 is found in the PC (CNT cells) of the CNT but also may be in the initial collecting duct of the rabbit. On the RNA level, BK- 2 and BK- 3 are expressed in either the PC or IC of the CCD. BK- 4 is expressed in the IC of the CNT and CCD.
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POTENTIAL MECHANISMS OF FLOW-MEDIATED ACTIVATION OF BK CHANNELS; n  [3 h. w' S) Z1 |

Initially, flow-mediated K secretion was explained as a consequence of changes in electrochemical driving forces (increased Na delivery to the distal nephron, and dilution of K in the lumen). However, it was subsequently shown that flow was an independent stimulator of K secretion ( 52 ), suggesting that factors intrinsic to increased flow, such as mechanical bending of cilia or release of a localized stimulating signal, was involved in enhancing K secretion. Intriguingly, membrane stretch induced by patch suction activates BK ( 101 ). However, stretch by suction produces cytoskeletal changes that mimic cell volume increases. Such stretch forces are probably different from the lateral forces induced by shear stress. Therefore, the relevance of membrane stretch-induced activation of BK in the context of flow-mediated K secretion is uncertain.9 K# G% C# u0 n- E1 Z* V

Although the P o of BK channels is very low when measured in the artificial condition of the split-open tubule, the P o of BK may be higher under (in vivo) conditions of fluid flow in the CNT. If BK channels are poised at the steep part of the activation curve (see Fig. 3 ), small increases in voltage may have large effects on the P o of BK. Because of a very large single-channel conductance, BK channels have the potential to secrete large quantities of K in response to flow.; ]& G; A  B$ w- P

At least two mechanisms are likely candidates. First, BK channels are Ca 2  sensitive, and it is known that intracellular Ca 2  increases with increased flow in the distal nephron ( 47 ). Indeed, flow and shear stress in the CCD increase [Ca 2  ] i in both PC and IC to 340 nM ( 111 ). Although there are no relevant BK channel data from the distal nephron for comparison, the BK channel of mesangial cells contains the same subunits as CNT channels (BK- 1). Mesangial cell BK are activated to a P o 0.2 at 300 nM Ca 2  with 0 mV across the plasma membrane (see ELECTROPHYSIOLOGY OF BK SECRETION ) ( 84 ). Because the single-channel conductance of BK is near 200 pS, a P o of 0.2 would be the equivalent of incorporating two ROMK channels in the apical membrane. Therefore, it is possible that increases in intracellular Ca 2  (either global or localized) may result in physiologically relevant activation of BK channels that contain the 1-subunit. Second, BK channels with the 1-subunit open dramatically in response to cGMP ( 41 ), and nitric oxide synthase is activated with increases in flow in the TAL ( 69 ). Therefore, increased nitric oxide (NO) may activate the BK channel through the PKG pathway. In addition, a phosphorylated BK channel is activated by much lower [Ca 2  ] i ( 38, 76 ). Possibly, these two mechanisms work synergistically to increase BK current under conditions of increased flow. As mentioned above, the 1-subunit of the BK channel confers PKG activation to BK ( 41 ) and dramatically increases the Ca 2  sensitivity of the channel ( 9 ). If flow-mediated K secretion does involve cGMP, or Ca 2  -mediated activation of BK, this may explain why flow-mediated K secretion is blunted in BK- 1 -/- mice ( 73, 74 ).
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K SECRETION IN THE CNT4 _( g7 a  c9 X" d. |% Y; P

The precise localization of BK- 1 to the CNT warrants a discussion of the role of the CNT in K secretion (for a more detailed and thorough discussion of this subject, see Ref. 57 ). The role of the CCD in K secretion has been investigated more extensively than that of the CNT, because of the greater accessibility and ease of dissection of the CCD. However, connecting tubules secrete K at much higher rates than CCDs ( 36, 75 ). Indeed, micropuncture studies that compared the [K ] of the distal tubular fluid along the length of the DCT, CNT, and ICT with the [K ] in the final urine showed that the majority of K is secreted before the main collecting duct segment ( 53, 54, 75 ). In fact, these studies found no net K secretion distal to the CNT/ICT. Similarly, the Na reabsorptive capacity of the CNT is several times higher than that of the CCD ( 18 ), and the density of SK (ROMK) channels in the CNT exceeds that in the CCD ( 17 ). Furthermore, when rats are fed a high-K diet ( 91 ) or rabbits are fed a low-Na /high-K diet ( 35 ), the height and the basolateral membrane area of CNT cells were increased, demonstrating the importance of this segment for K transport. These data all indicate that the CNT is a primary site of Na and K handling. As a further (in vivo) confirmation of these data, it was found that mice with a CCD-specific knockout of the -subunit of ENaC (the apical Na reabsorptive channel of the distal nephron) are able to maintain normal Na and K balance ( 78 ). In fact, the handling of Na and K in these animals is indistinguishable from wild-types, even when challenged with salt restriction, water deprivation, or K loading. However, the converse experiment, ablating the -subunit of ENaC in the CNT, has not been performed. Nevertheless, the authors of this study concluded that more proximal nephron segments, such as the late DCT and CNT, must play a prominent role in Na and K handling. This is further supported by the fact that the CNT contains both Na and K channels in the apical membrane, has an abundance of mitochondria, has a highly amplified basolateral membrane, and expresses the highest levels of the enzyme 11 -hydroxysteroid dehydrogenase (necessary for the action of aldosterone, the primary hormone for regulating K secretion) ( 7, 57, 87 ). Its location directly downstream of the TAL makes the CNT well positioned to respond to increased flow with enhanced K secretion.& C9 `& N# @$ E+ D" c0 j

DIETARY AND HORMONAL INFLUENCES ON BK-MEDIATED K SECRETION  ^9 x" e6 s% v

Although few studies have addressed a potential role for BK channels in the distal nephron other than mediating flow-induced K secretion, recent studies have provided evidence for additional roles for the BK channel in the distal nephron. A study of the effect of arginine vasopressin (AVP) on K secretion using micropuncture found that the luminal effect of AVP appears to be mediated by BK channels ( 1 ). This study also demonstrated that AVP acts on BK channels via the V1 receptor and the PLC/Ca 2  /PKC signaling pathway. Studies in other tissues have shown that the BK- 1 subunit is required for PKC-mediated modulation of BK channel current (in response to Ca 2  transients) ( 28 ). Therefore, the presence of BK- 1 in the CNT may allow BK channels to respond to AVP/PKC signaling.3 E# p8 Z: D  `) V

In addition to a role in responding to AVP, there is evidence that BK channels may have a role in the renal response to aldosterone and/or a high-K diet. Although BK- -/- mice maintain normal plasma [K ] while on a high-K diet, their plasma aldosterone concentrations are dramatically increased ( 77 ). Indeed, the aldosterone concentrations of these mice were also significantly increased under conditions of a low- or normal-K diet. Therefore, in the absence of BK, aldosterone is stimulated to eliminate K by another channel/mechanism. A separate micropuncture study demonstrated that the increase in renal K secretion associated with a high-K diet was largely blocked by a specific BK channel inhibitor (IBTX) ( 4 ). Although enhanced ROMK activity has been shown to play an important role in the increase in K secretion associated with a high-K diet ( 44, 105 ), it now appears that the BK channel may also participate in this phenomenon.

At least one study shows that aldosterone alters trafficking to increase ROMK current ( 115 ). However, this may not be the case for BK. Two patch-clamp studies, one in rabbit distal colon ( 26 ) and one using primary cultures of rabbit CCD ( 45 ), demonstrated that aldosterone stimulation [either by a low-Na diet ( 26 ) or directly ( 45 )] did not alter the density of BK channels. However, a recent study ( 65 ) using the isolated, perfused CCD demonstrated an increase in apical membrane expression of BK channels when rabbits were placed on a high-K diet. It is therefore uncertain whether the high-K diet-mediated increase in K secretion indicates an effect of aldosterone on BK channel P o or an effect of aldosterone/high K on BK channel targeting to the cell surface.

Interestingly, it was shown with patch-clamp methods that a high-K diet resulted in an increased density of ROMK in the CCD, but not the CNT (where the majority of physiological K secretion takes place) ( 17, 71 ). However, the CNT does exhibit a very large increase in Na channel (ENaC) density with a high-K diet, consistent with the large negative transepithelial potential (-75 mV; see ELECTROPHYSIOLOGY OF BK SECRETION ) reported in this segment ( 19 ). It has been suggested that the enhanced K secretion in the CNT results from the depolarized apical membrane potential due to the large incorporation of Na channels. Although patch-clamp studies did not report a high K -induced increase in BK channels in the CNT of rats ( 17 ), micropuncture studies using IBTX revealed an increased BK-mediated K secretion in mice on a high-K diet ( 4 ). Therefore, although a high-K diet does not affect the number of apical membrane ion channels in the CNT, the very large increase in Na channel incorporation and depolarization of the apical membrane potential may be enough to activate BK in a perfused tubule. This may explain why flow-mediated K secretion is particularly notable when plasma K concentration is normal or high. With higher concentrations of plasma K  , increased mineralocorticoid levels will cause Na channel incorporation with a large apical membrane depolarization in the CNT, which allows BK to more readily open in response to other signals, such as an increase in Ca 2  concentration.; p1 @6 y. R# d" _
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In the CCD, however, a high-K diet may enhance ROMK-mediated K secretion (as opposed to BK-mediated K secretion) because there is less incorporation of ENaC, and therefore less apical membrane depolarization to activate BK. Moreover, because of the absence of the BK- 1 subunit in the CCD, a much larger depolarization would be required to activate BK in this segment (see Fig. 5 ). It appears, then, that both ROMK and BK may have a role in secreting large amounts of K after exposure to a high-K diet. The BK channels in the CNT, already present in the apical membrane, may be well placed to be early responders to a high-K diet, whereas ROMK channels in the CCD may respond slightly later due to the time required for apical membrane insertion.
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Fig. 5. Cell potential profiles and cell models showing the relative transport of K across the CNT cells in control and high-mineralocorticoid conditions.

ELECTROPHYSIOLOGY OF BK SECRETION
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Early studies employing the patch-clamp technique concluded that BK channels are not likely to contribute to physiological K secretion due to the low basal P o of these channels in the cell-attached configuration in CCD PC. However, we now know that flow-mediated K secretion takes place primarily in the CNT PC, where the 1 subunit confers increased P o to BK ( 74 ). It is thus important to examine in some detail whether BK- 1 plays a role in K secretion.3 |1 `6 @- O/ {+ z' f
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To examine the feasibility of a role for BK channels in renal K secretion, it is necessary to consider the potential for K secretion from an electrophysiological standpoint. In this section, we will first examine the electrophysiological considerations for K secretion in the CCD and CNT and then relate these considerations to electrophysiological properties of the BK channel. We will examine the electrophysiology of K secretion in the PC of the CCD and the CNT in normal conditions and when mineralocorticoid levels are elevated, either with mineralocorticoids or by a high-K diet. The probability of K secretion in IC- and IC- will also be discussed.+ _! s4 [  F) C3 p6 N7 T  n

Microelectrode studies verified the net transport rates for Na and K previously described for the mammalian CCD using isotopic or chemical measurements of luminal [Na ] and [K ]. However, microelectrode methods also enabled the dissection of the separate contributions of the conductances and electrochemical forces that determine the rates of Na and K transport across the apical, basolateral, and tight junction barriers. Two major assumptions were made at that time. First, the IC could be modeled as part of tight junction conductance, which implies that the resistance of these cells is very high compared with PC. Indeed, although BK channels have been identified in IC with patch-clamp techniques, there is no evidence that the apical membrane of IC have significant Na - and K -conductive pathways and current flows ( 99 ). The second assumption was that the CCD secretes K into a lumen that contained 5 mM K  . This second assumption seems to be invalid; although the CCD is capable of K secretion, as demonstrated by several studies, a luminal concentration of 5 mM K would be observed only under extreme diuretic conditions. In fact, mathematical models ( 108, 109 ) as well as functional data ( 53, 55 ) indicate that in vivo luminal [K ] is already 22 mM at the end of the CNT. By the time the filtrate reaches the more distal portions of the CCD, the luminal [K ] is closer to 30 mM, and the electrochemical forces may bring K secretion to a static head or even favor K absorption in this segment ( 54, 55, 75, 109 ).8 Z" U3 e. g1 }6 O5 e* e* H

In the following analysis, membrane potentials and currents were calculated based on experimental data provided by a variety of laboratories ( 39, 64, 67 ). Our calculations and estimates are based on data obtained primarily from the rabbit CCD and CNT. These estimates allow for a comparison of K transport rates in the CCD and the CNT under control and stimulated (mineralocorticoid) conditions. In this analysis, we will demonstrate that although BK channels have a very low P o when examined in the distal nephron by patch clamp (an artificial situation), given the known properties of the channel and the expected in vivo conditions (i.e., transepithelial potential, etc.) it can be calculated that BK channels are likely to be open to an extent that they could play a significant role in K secretion (especially under conditions of mineralocortocoid stimulation).
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CCD PC! u  l% `5 T% p0 Q; K6 W5 b

For the purpose of our analysis, we have used data obtained in isolated, perfused CCDs of rabbits ( 39, 67 ). The initial studies in rabbit CCDs were shortly followed by microelectrode studies of CCDs isolated from the rat ( 86 ). For our analyses, we assume that currents across membranes obey Ohm's law, that there is a straight-line relationship between the driving force and the current.' \3 W2 k  V& g& g3 R

The driving force across the apical membrane of the PCs is a combination of the chemical potential for K ( E K ) and the apical membrane potential ( V a ), the latter being a calculation from the transepithelial potential ( V te ) minus the basolateral membrane potential ( V b ). Figure 4 depicts the cell potential profiles and cell models, including K transport across the CCD PC in control and high-mineralocorticoid conditions.

Fig. 4. Cell potential profiles and cell models showing the relative transport of K across the CCD principal cells in control and high-mineralocorticoid conditions. V te, V a, and V b : transepithelial, apical membrane, and basolateral membrane potential, respectively; I K, K current.
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In control conditions, V te has been measured as -15 mV and the V a of the CCD PC has been reported at -80 mV with 5 mM K in the lumen ( 39, 68 ). It should be noted, however, that the physiological concentration (after water extraction) of K at the midpoint of the CCD has been estimated to be closer to 30 mM ( 109 ). This concentration in the lumen will change the E K and also will depolarize the V a, owing to the preferential membrane permeability to K over Na ( 39, 83 ). Thus, using a [K ] of 30 mM in the lumen, V a can be estimated by the transference number (T f ) of the apical membrane. The increase in luminal [K ] from 5 to 50 mM depolarizes the apical membrane by 40 mV, which equates to a T f of 0.67 in control conditions, and by 33 mV (T f = 0.55) in mineralocorticoid-treated tubules ( 39, 83 ). The decreased T f in mineralocorticoid conditions reflects the fact that the Na conductance increases more than the K conductance ( 39 ). For our analysis, we used a K conductance value of 4 mS/cm 2 in control and 8 mS/cm 2 in mineralocorticoid-stimulating conditions ( 83 ). We used 120 mM as the intracellular [K ] in both control and mineralocorticoid-stimulated conditions as reported for CCDs isolated from rabbits ( 81 ).
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As shown in Fig. 4, in the CCD the electrochemical gradient favors K absorption in control (low aldosterone and antidiuretic) conditions in which the luminal [K ] is 30 mM. This conclusion is consistent with micropuncture sampling of the end of the late distal tubule of control rats, which demonstrated that net K absorption occurs between this site and the final urine ( 54 ). In contrast, V a is depolarized enough in high-mineralocorticoid conditions, due to increased Na transport, to permit significant K secretion. This is consistent with the notion that the mammalian CCD is capable of secreting additional K when stimulated substantially by mineralocorticoids. In high-aldosterone/high-K diet conditions, K secretion in the CCD may be the result of inserting ROMK channels in the apical membrane ( 72 ). On the other hand, during K conservation, ROMK, with a higher conductance of 50 pS for inward currents, may be a good candidate for absorption of K in the CCD.0 q% Z; v( v" K5 G) T' Y
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CNT Cells

As mentioned in earlier sections, the CNT has a much larger capacity for K secretion than the CCD ( 36 ). The Na and K transport properties of CNT cells are qualitatively similar to the those of the CCD, although the magnitude of Na and K transport per square centimeter is three to four times greater. The V te of -45 mV across the isolated perfused CNT in control rabbits ( 102 ) is three times the V te of the CCD, reflecting the much greater Na transport in this segment. V b has been measured in rabbit CNTs under control but not high-mineralocorticoid conditions ( 63 ). For these calculations, we assume that V b and V a are the same as in the rabbit CCDs treated with mineralocorticoids. Figure 5 illustrates the cell potential profiles and cell models showing the magnitude and direction of K current in the CNT. Assuming that the mid-CNT [K ] is 12 mM ( 108 ), intracellular [K ] is 120 mM, and the K conductance is 4 mS/cm 2, the K current across the apical membrane under control conditions would be -156 µA/cm 2, a magnitude much greater than the CCD value of -57 µA/cm 2, estimated under mineralocorticoid-stimulated conditions. This reflects the much greater transport activity in the CNT.& E% F: l% ?- f$ I0 x

In high-mineralocorticoid conditions, the V te across the late distal tubule is approximately -75 mV ( 113 ), indicating high Na transport rates in the CNT, and a very large depolarization of the apical membrane potential to 10 mV, which is the result of a more than fourfold increase in apical Na (ENaC) channels ( 17 ). Although the K conductance has not been determined in the CNT under high-mineralocorticoid conditions, it will be assumed that the K conductance is increased to 8 mS/cm 2, as found in the CCD. This driving force yields a current of -464 µA/cm 2.1 {1 b2 }" w' N  a1 k# a4 p$ _
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Table 1 shows the range of values obtained from various micropuncture studies for V te and K secretion in the K -secreting tubule segments of rats. These fluxes are compared with those based on electrophysiological data. The calculated currents were converted to fluxes using Faraday's number. The "high-K  " values were obtained from rats given an acute K load, known to stimulate endogenous mineralocorticoid secretion. The resulting K secretory values are similar to those obtained with either aldosterone or synthetic mineralocorticoid treatment, but are less than the values obtained by long-term K adaptation ( 90 ). As shown in Table 1, the calculated K secretory fluxes ( row 4 ) in control and high-K (or mineralocorticoid)-stimulated conditions are larger than the values for K transport obtained by directly measuring [K ] in the luminal fluid ( row 2 ). However, the calculated relative threefold increase in K secretion in the CNT after mineralocorticoid stimulation is close to that found experimentally ( 15, 92 ). The higher calculated values may be due to an overestimate of the actual CNT tubule length in the micropuncture studies. 1 As shown in row 3 of Table 1, when the flux values are corrected for effective area of K secretion, the range of flux measurements are close to the calculated currents.
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Table 1. Comparison of in vivo measured and electrophysiologically calculated J K across the late distal/CNT in control and high-K or high- mineralocorticoid conditions

The discovery of BK channels in IC by patch clamp ( 70 ) has led to the suggestion that flow-induced K secretion is mediated by IC. However, electrophysiological evidence for a role of BK in K secretion in IC is very conflicting. Measurements of V te and cell potentials with microelectrodes show that the V a is more depolarized in IC than PC ( 62, 64 ), which would be expected to activate voltage-sensitive channels such as BK. However, microelectrode measurements ( 64 ) indicate that there may not be substantial K conductance in the apical membrane of IC, even under high-flow conditions.
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The assessment of the role of the IC in K secretion in the distal nephron is further complicated by the presence of at least two types of IC, IC- and IC-, which are differentially distributed in the CNT and CCD ( 64 ). However, these cells are electrophysiologically identical in the CNT and the CCD. In both CNT and CCD, the V b of IC- and IC- is approximately -35 mV and unaffected by mineralocorticoids ( 64 ). The low V b in IC in both normal and mineralocorticoid-stimulated conditions suggests that the Na -K -ATPase activity is very low and probably involved in housekeeping (cell volume regulation) but not in setting the gradient for K secretion in these cells.
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The V a of IC is more depolarized than the V a of PC and may be as high as  40 mV in high-mineralocorticoid conditions. However, a pathway for flow-mediated K secretion in the IC was not detected by microelectrode studies designed to discern the separate conductive properties of the apical and basolateral membranes of the IC of the CCD ( 62 ) and CNT ( 64 ). For IC of the CCD, it was found 0.95, indicating that the conductive pathways across the IC apical membrane were minimal ( 64 ). Similarly, for the CNT, it was found that the V a of IC- and IC- did not change after luminal [K ] was increased from 5 to 50 mM, demonstrating the absence of detectable K conductance in the apical membranes of these cells ( 64 ). The depolarized cell potential in ICs is the result of the absence of a K conductance in the apical membrane and consistent with the absence of ROMK channels in cell-attached patches ( 114 ). In contrast, V a of the CNT (PC) cells changed by approximately  30 mV when luminal [K ] was raised from 5 to 50 mM, demonstrating the predominant apical K conductance of the CNT cells ( 64 ). 15 nl/min, a rate shown to maximally stimulate BK in the CNT ( 36 ), suggests that BK channels in IC are not activated by flow. The failure to detect flow activation of an apical [K ] in IC can be explained by an association of the BK- 4 subunit with the BK-. As shown in Fig. 3, even at  40 mV, the BK of IC would require 1 µM Ca 2  to activate to a P o of 0.1. That the Ca 2  only increases to 340 nM in IC with flow ( 111 ) may explain the undetectable apical K conductance in IC using microelectrode techniques. Another study was unable to detect BK- in IC using a radiolabeled double mutant analog of IBTX ( 25 ). The lack of IBTX binding in IC could be explained by the association of BK- with the BK- 4 subunit, which renders the BK- resistant to IBTX ( 56 ). However, these investigators also used immunohistochemistry and were unable to localize BK- to IC. This result was different from a previous study that detected BK- in IC using immunohistochemistry with a different antibody ( 65 ). It is possible that the former study used an antibody that recognized a sequence in a BK- splice variant that is not expressed in IC.

Although microelectrodes did not detect an apical membrane conductance in isolated CNT or CCDs perfused at high flow rates, it is possible that BK- 4 channels in IC are activated by a mediator only present in tubular fluid in vivo. However, even if activated in vivo, transport via BK would be limited because the amount of Na-K-ATPase protein in IC of the CNT, which is 12% of the value in CNT cells (PC), is only enough for housekeeping purposes ( 79 ).7 `- C# d2 n9 I) U& K3 w- y/ N; r9 Y
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Previous studies have reported that BK channels appear to be expressed at a higher density in IC vs. PC ( 70 ). A recent study demonstrated that MAPK may play a role in the increased functional expression of BK in IC vs. PC. Patch clamping revealed the appearance of BK in 8% of PC and 28% of IC. However, inhibition of both Erk MAPK and P38 MAPK increased the observations of BK in PC to 28% without affecting the percentage of observed BK in IC ( 43 ). Thus the constitutive inhibition of BK by MAPK may also explain the absence of observing BK in PC by patch clamping.+ @+ [& Q6 `- L& G2 x! \+ z* m) @, M* K" u

Electrophysiology of K Transport via ROMK vs. BK
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At resting V a in the CNT, ROMK channels are open constitutively with a P o of 0.80. With a density of two channels/patch, an approximate area of 1 µm/patch, and a single-channel conductance of 30 pS (outward currents), ROMK can account for 6 mS/cm 2, a value close to the K conductances of 4 and 8 mS/cm 2 used to calculate the K current in the CNT in control and high-mineralocorticoid conditions, respectively. This is in agreement with a recent study in which it was calculated that ROMK could account for the observed K conductance in the CCD ( 22 ).
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The BK channel has complex intrinsic activating properties, and therefore it is difficult to assess its potential role in K secretion under various conditions. The single-channel conductance of BK is at least five times greater than ROMK for outward currents. Therefore, at the same P o, BK can secrete the same quantity of K at a much lower density of channel expression in the apical membrane. However, the potential for BK to open depends largely on the associated -subunit." `# W5 W2 h2 u
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Figure 3 shows the strong influence of the BK- 1 subunit, with plots of voltage vs. P o ([Ca 2  ] i = 0.8-1 µM) of BK, assessed by the total conductance of each channel normalized to its maximal conductance ( 12 ). In the presence of the BK- 1 subunit, which is uniquely expressed in CNT PC, the voltage-activation curve for BK is shifted by -75 mV (see Fig. 5 ) ( 12 ). During high distal flow, an increase in [Ca 2  ] i to 340 nM would activate BK- / 1 to a P o of 0.2. Furthermore, local Ca 2  concentrations 340 nM with high flow.$ r3 Y; I/ B+ i6 b1 U
7 u' @8 x/ F& @7 T4 h" ^
The V a of both IC- and IC- are normally 30 mV more positive than PC. However, as shown in Fig. 3, an association of the 4-subunit means that these cells require a depolarization of 140 mV more than the BK- / 1 channels of the PC/CNT cells for similar activation. Indeed, it was shown ( 70 ) that brief openings of BK in cell-attached patches of rabbit IC required patch potentials of 100 mV. This large depolarizing potential required to activate BK is consistent with the finding that the BK- 4 subunit is associated with the BK- in IC.
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DIVISION OF LABOR

This review has highlighted the potential roles of the BK channel in K secretion. However, it is important to note that ROMK and BK play complementary roles in K secretion, with a division of labor such that each channel contributes according to its specific properties (see Fig. 6 ). ROMK, with a high P o under resting conditions, is likely the primary contributor to basal K secretion. BK channels, with an extremely high conductance (and therefore a high capacity for K secretion) but a low P o, are available for activation when additional K secretion is demanded of the kidney. However, it is likely that these roles are far from definitive and that in fact there is significant overlap in the functional roles of these two channels.( s$ F5 t+ g5 I+ r$ a
# ]6 O2 ^$ o; T- \7 z0 i: t
Fig. 6. Summary figure showing the proposed roles of secretory K channels in the CNT. Under basal conditions, ROMK is likely the primary channel involved in K secretion. Under conditions where increased K secretion are demanded (increased flow, high aldosterone, etc.), it is proposed that both ROMK and BK play a role. ROMK likely contributes through an increase in the number of channels on the apical membrane, whereas a more likely mechanism for BK is the activation of existing channels. The larger conductance of BK (compared with ROMK) implies that a relatively "small" number of BK channels may make a very significant contribution to K secretion. The fact that BK- 1 is not expressed on IC implies that BK channels in IC are not involved in K secretion.( @( l! m1 e4 G+ W- B" f
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The critical role that each channel plays in renal K handling is highlighted in type II Bartter's syndrome patients. These patients, lacking functional ROMK channels, may develop dangerously low plasma K values. This hypokalemia is probably due to the absence of ROMK from the TAL, resulting in flow-mediated activation of BK. However, strikingly, as infants these patients have a transient hyperkalemia during the first week of postnatal life ( 16 ). This is likely due to the fact that ROMK channels are functionally expressed sooner than BK channels ( 20, 111 ). Notably, type II Bartter's (ROMK mutation) is the only variant of Bartter's associated with early hyperkalemia. In early postnatal life, these patients have neither BK (due to the normal delay in channel expression) nor ROMK (due to the Bartter's syndrome mutation), resulting in profound hyperkalemia. As BK channel expression begins, patients develop hypokalemia due to the excessive flow-mediated activation of BK channels. This unique scenario elegantly highlights the critical role that each channel plays in renal K handling.
! ^9 L2 `( y! J" a, _& R0 q
In conclusion, recent evidence has demonstrated that both ROMK and BK channels play a role in K secretion. Future studies will likely focus on the CNT segment and the in vivo contribution of each of these channels to renal K handling./ M/ M0 C9 Z  _% t% z5 i

GRANTS( g# r  P# ~; O/ T1 k" [
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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1-DK-49561 (to S. C. Sansom) and 5T32-DK-007259-26 (Training Grant to J. L. Pluznick).# x- }: a$ s- h! ~6 L% V' T

ACKNOWLEDGMENTS

We thank Dr. Gerhard Giebisch for critical comments and suggestions for improving this review.9 Y* }' |& S0 _1 Q" }4 O2 `
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