INVITED REVIEW
ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells

Hisashi Yokoshiki, Masanori Sunagawa, Takashi Seki, and Nicholas Sperelakis

Department of Molecular and Cellular Physiology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0576

    ABSTRACT
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Abstract
Introduction
Summary
References

ATP-sensitive K+ (KATP) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is because stimulation of KATP channels is thought to produce vasorelaxation and myocardial protection against ischemia, whereas inhibition facilitates insulin secretion. It is well known that native KATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nucleotide diphosphates and K+ channel-opening drugs (KCOs). Although these characteristics can be shared with KATP channels in different tissues, differences in properties among pancreatic, cardiac, and vascular smooth muscle (VSM) cells do exist in terms of the actions produced by such regulators. Recent molecular biology and electrophysiological studies have provided useful information toward the better understanding of KATP channels. For example, native KATP channels appear to be a complex of a regulatory protein containing the SU-binding site [sulfonylurea receptor (SUR)] and an inward-rectifying K+ channel (Kir) serving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been cloned and found to have two nucleotide-binding folds (NBFs). It seems that these NBFs play an essential role in conferring the MgADP and KCO sensitivity to the channel, whereas the Kir channel subunit itself possesses the ATP-sensing mechanism as an intrinsic property. The molecular structure of KATP channels is thought to be a heteromultimeric (tetrameric) assembly of these complexes: Kir6.2 with SUR1 (SUR1/Kir6.2, pancreatic type), Kir6.2 with SUR2A (SUR2A/Kir6.2, cardiac type), and Kir6.1 with SUR2B (SUR2B/Kir6.1, VSM type) [i.e., (SUR/Kir6.x)4]. It remains to be determined what are the molecular connections between the SUR and Kir subunits that enable this unique complex to work as a functional KATP channel.

adenosine 5'-triphosphate-sensitive potassium channels; sulfonylurea receptor; inward-rectifying potassium channel; nucleotide diphosphates; potassium channel-opening drugs

    INTRODUCTION
Top
Abstract
Introduction
Summary
References

SINCE THE FIRST DISCOVERY of ATP-sensitive K+ (KATP) channels in the heart in 1983 (115), accumulating studies have shown that similar types of K+ channels are present in many tissues, including pancreatic beta -cells, skeletal muscle cells, vascular and other smooth muscle cells, neuronal cells, endothelial cells, and renal epithelial cells (5, 8, 38, 123, 144). In the experiments by Noma (115), metabolic inhibition produced by cyanide unmasked K+ channels that were normally inhibited by ATP at the inner surface of the membrane. Thus they were designated as KATP channels. In the normal heart, the KATP channels are masked (closed, inhibited) by the high intracellular ATP concentration ([ATP]i) and become unmasked (opened, disinhibited) during ischemia (lowered [ATP]i), thus serving to protect ischemic myocardial cells. That is, increasing the total outward K+ current shortens the action potential duration and thereby decreases Ca2+ influx and contraction and so conserves ATP. The physiological and pharmacological properties of KATP channels have been intensively examined, especially in cardiac and pancreatic tissues. Their unique properties include stimulation by nucleotide diphosphates (NDPs) and K+ channel-opening drugs (KCOs) and inhibition by sulfonylurea (SU) compounds as well as by ATP (through a ligand-action) (Table 1).

                              
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Table 1.   Major regulators of KATP channels

On the other hand, the depolarizing action of SU compounds on pancreatic beta -cells, with enhanced insulin secretion, had been recognized earlier (29), and these compounds have been used for treatment of patients with non-insulin-dependent diabetes mellitus (NIDDM). It was reported in 1985 (141) that low doses of SU compounds were specific blockers of KATP channels (14, 46, 152). Pursuant to the cloning of the protein that contains the SU-binding site [i.e., sulfonylurea receptor (SUR)], it has been recently suggested that KATP channels are composed of two proteins: SUR and Kir, the latter being a member of the inward rectifier K+ channels (1, 3, 4, 54, 55, 65, 66, 68, 114, 129, 153, 159). In this review article, we briefly summarize the characteristics and the proposed structures of KATP channels in cardiac, vascular smooth muscle (VSM), and pancreatic beta -cells. We recommend several excellent review papers on this topic (5, 8, 38, 144).

    PHYSIOLOGICAL ROLES OF KATP CHANNELS

Physiological roles for KATP channels have been suggested in many tissues. For example, KATP channels in the resting pancreatic beta -cells are usually active during fasting (2-3 mM blood glucose), and they set the membrane potential close to the K+ equilibrium potential (EK), thereby reducing their excitability and insulin secretion (i.e., excitation-secretion coupling). Increase in blood glucose (5-7 mM) after a meal raises [ATP]i, which results in closure of KATP channels, thereby depolarizing the plasma membrane of beta -cells. Such depolarization increases intracellular Ca2+ concentration ([Ca2+]i) largely through activation of voltage-gated Ca2+ channels. The rise in [Ca2+]i triggers exocytosis of insulin granules, thereby stimulating the release of insulin (98) (Fig. 1, A and B).


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Fig. 1.   ATP-sensitive K+ (KATP) channel as a major regulator of insulin secretion. A: KATP channels in the resting pancreatic beta -cells are usually active during fasting (2-3 mM blood glucose); they set the membrane close to K+ equilibrium potential, thereby reducing their excitability and insulin secretion. PNa/PK ratio, ratio of Na+ permeability to K+ permeability; Kir, inward-rectifying K+ channel subunit; SUR, sulfonylurea receptor; skel., skeletal tissue; m., muscle tissue; Hyperpol, hyperpolarization; dec, decrease; metab, metabolism. B: increase in blood glucose after a meal raises intracellular ATP concentration ([ATP]i) and results in closure of KATP channels, thereby depolarizing the plasma membrane of beta -cells. Such depolarization (Depol) increases intracellular Ca2+ concentration ([Ca2+]i), largely through activation of voltage-gated Ca2+ channels. Rise in [Ca2+]i triggers exocytosis of insulin granules, thereby stimulating insulin secretion. inc, Increase; rel, release.

Depolarization of arterial myocytes by glibenclamide, an SU compound, has been reported in various intact arterial smooth muscle tissues, including small mesenteric (97, 102, 107, 157), coronary (37), and vertebral (104) arteries. For example, in the rabbit vertebral artery, glibenclamide (1 µM) depolarized the membrane by 23 mV and markedly potentiated histamine-induced contraction (104). In addition, application of glibenclamide to the coronary artery of anesthetized dogs increased coronary resistance and reduced coronary blood flow (64, 131), suggesting that functioning KATP channels are present under physiological conditions (28, 30). This suggests that, at least in some VSM tissues, KATP channels may be acting as an important background K+ conductance, which helps to regulate vascular tone.

Opening of cardiac KATP channels is thought to protect against myocardial damage from ischemia, largely due to reduction in Ca2+ influx and energy preservation. The use of KCOs during cardioplegia was suggested to prevent the high K+ concentration (16 mM) (used during cardioplegia) from producing the observed Ca2+ loading of cardiac myocytes (93, 94). [The mechanism for this protection is not understood because, theoretically, KCOs should have almost no effect on resting membrane potential of myocardial cells at extracellular K+ concentration levels of 16 mM (137).] Channel activation was suggested to be a mechanism responsible for ischemic preconditioning (103), i.e., a brief period of ischemia lessens the amount of myocardial damage produced by a subsequent prolonged ischemia. For example, ischemic preconditioning was mimicked by KCOs and was abolished by glibenclamide (56, 101, 132). On the other hand, other factors, such as adenosine (58, 90), protein kinase C (PKC; Refs. 92, 136, 164), and Ca2+ (100), were reported to trigger ischemic preconditioning. Although the end effector that produces ischemic preconditioning has yet to be determined, the KATP channels are targets of stimulation by factors known to induce ischemic preconditioning (63, 75, 81, 89, 91, 147). Therefore, activation of KATP channels may represent a common pathway of the ischemic preconditioning.

The phenomenon of ischemic preconditioning is thought to occur in human myocardium (78, 156, 160) and was reported to be abolished by glibenclamide, a blocker of KATP channels (22, 150). In NIDDM patients receiving tolbutamide (the University Group Diabetes Program; Ref. 76) or other SU compounds (128, 135), the loss of this protective mechanism, with possible resultant coronary vasoconstriction (17; see above) might account for the increased incidence of cardiovascular accidents.

KATP channels are also present in other tissues, including skeletal muscles, nonvascular smooth muscles, neurons, endocrine cells (e.g., adenohypophysis), renal cells, vascular endothelial cells, and follicular cells of the ovary (38, 86, 123, 144). For example, in patients with myotonia congenita and periodic paralysis, hyperpolarization of the skeletal muscle fibers produced by KATP channel opening not only abolished spontaneous twitches and aftercontractions but also increased the force of twitch contractions (53, 124, 138). This suggests that KATP channels in skeletal muscles help to regulate their excitability, especially in diseased fibers. In most endocrine cells, hormonal secretion (e.g., growth hormone, cholecystokinin, insulin) is stimulated by depolarization (excitation-secretion coupling) (16, 96). In contrast, in the juxtaglomerular cells of the vas afferens (kidney), hyperpolarization (due to opening of KATP channels) increases renin secretion (41, 123). This mechanism might be related to a decrease in [Ca2+]i produced by hyperpolarization, because renin secretion was reported to be inversely coupled to the level of [Ca2+]i (57, 123). In the renal tubular system, KATP channels have been found in the proximal tubule, thick ascending limb of Henle's loop, and cortical collecting duct. These channels are active under physiological conditions, producing K+ efflux on either the basolateral side (in the proximal tubule) or the luminal side (in the ascending limb and collecting duct). Thus KATP channels play an important role in the reabsorption of electrolytes and solutes as well as in K+ homeostasis (123). In endothelial cells, KATP channels serve as a regulator of the resting potential during energy impairment and may modulate the release of endothelium-derived relaxing factor under such conditions (69, 72, 73, 84).

    REGULATION OF KATP CHANNELS

KATP channels in pancreatic beta -cells are known to be inhibited by ATP, with a half-maximal inhibitory concentration (IC50) ranging from 15 to 40 µM (6, 23, 117, 126). Because [ATP]i in beta -cells is above ~3 mM even in the absence of glucose (10), in principle, all KATP channels should be closed under resting conditions. However, perforated-patch recordings have revealed that some [i.e., ~10% (8)] KATP channels could be active (despite the relatively high [ATP]i) and could determine the major background conductance (in the absence of glucose) (8, 134). Therefore, other regulators in addition to ATP have been suggested to govern the activity of KATP channels.

Relatively high doses (1-4 mM) of ADP produced inhibition of cardiac KATP channels in the early study by Noma (115), which suggested that ADP has some affinity to the ATP-binding inhibitory site (ligand action) but has a low potency. However, this inhibitory action of ADP is usually counteracted by a stimulatory action. That is, NDPs, such as ADP, UDP, and GDP, exert substantial stimulation of KATP channels in pancreatic, cardiac, and VSM tissues, especially in the presence of Mg2+ (12, 13, 33, 34, 42, 70, 85, 87, 118, 143, 154). This could be explained in part by the possibility that NDPs activate KATP channels by competing with ATP for binding to the channel (e.g., thus explaining the antagonistic effect of NDPs against ATP-mediated inhibition). Thus it is now believed that the ratio of ATP to ADP could be the important regulator that links the channel activity to cellular metabolism, i.e., a decrease in this ratio stimulates the channels. On the other hand, in the absence of ATP, NDPs can further stimulate KATP channel opening (33, 34, 70, 154), which indicates that there may be a mechanism other than competition between NDPs and ATP at the same binding site. For example, Tung and Kurachi (154) found that NDPs can restore channel activity after rundown (see below) and suggested that there is a specific NDP-binding site (N site; stimulatory) that keeps the channel in an operative state (see Fig. 2B).


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Fig. 2.   KATP channel as a complex of SUR and Kir channel subunits (A) and representations of proposed models of KATP channels for myocardial (B) cells and vascular smooth muscle (VSM) cells (C). A: reproduced in modified form [from Philipson (119) with permission. Copyright 1995 American Association for the Advancement of Science]. Ri, inhibitory regulatory protein. B and C: in this model, there are two functional gates, that is, A gate and N gate. See text for details.

In contrast to the inhibition produced by ATP (ligand action), KATP channel activity actually disappears gradually in ATP-free condition, and this phenomenon is called rundown. That is, when a membrane patch is excised from the plasmalemma into an ATP-free solution, after the initial vigorous openings, the activity of the KATP channels declines with time. This rundown could be reversed to some extent by reexposure to ATP, depending on both dose and duration. This action of ATP requires Mg2+, which suggests that MgATP maintains the channel activity through a hydrolysis-dependent action (including phosphorylation) (49, 117, 142) (Table 1; Fig. 2B, R site).

It has been widely recognized that there are several compounds that act to stimulate KATP channels, and they are called KCOs (38, 144). The actions of these agents are usually antagonized by SU compounds. Among the KCOs, nicorandil (classified as a pyridine) is a balanced arterial and venodilator and clinically available as an antianginal agent. Despite their common action of K+ channel opening, there are several subclasses of KCOs that are based on their chemical structures (38). In one proposed classification, the prototype KCOs, pinacidil, diazoxide, and cromakalim, are classified as pyridines, benzothiadiazines, and benzopyrans, respectively. Tissue-specific actions exist among the different subclasses of KCOs. For example, cardiac KATP channels are activated by similar concentrations of pinacidil and cromakalim (39, 106) but not by diazoxide (40). KATP currents in VSM cells are activated by all three agents, but with a lower potency of diazoxide (110, 125). However, diazoxide is the most potent in stimulating pancreatic KATP channels, compared with pinacidil and cromakalim (35, 51) (Table 2).

                              
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Table 2.   Properties of KATP channels in pancreas, heart, and VSM

Similarly, there are some tissue-specific differences in inhibitory actions by glibenclamide and tolbutamide, prototype SU compounds (Table 2). According to the latest idea that a complex of two proteins, i.e., SUR and Kir, forms the KATP channel, tissue differences in actions of KCOs, SU compounds, and ATP (see A COMPLEX OF SUR AND KIR constitutes the katp channel and Tables 2-4) may result from distinct isoforms of SURs as well as of Kir proteins.

It was also reported that KATP channels 1) were stimulated by G protein (Galpha i or Goalpha ) (75, 147), 2) were regulated by pH (24, 74, 87, 122), and 3) were regulated by phosphorylation with protein kinase A (PKA), protein kinase G (PKG), or PKC (63, 89, 91, 108). For example, application of active forms of exogenous G protein subunits (Galpha i-1, Galpha i-2, or Goalpha ) to the internal surface of the plasmalemma activated cardiac KATP channels that had been inhibited by ATP (147).

Open probability and single-channel conductance of cardiac (24) and pancreatic (122) KATP channels were reported to decrease when intracellular pH was lowered below 6.7 (in the absence of ATP). In contrast, in the presence of intermediate concentrations of ATP (~10-100 µM), acidosis (pH = 6.25-6.8) produced substantial stimulation of KATP channels, which could be accounted for by a shift in ATP sensitivity (74, 87, 122). For example, the IC50 value for ATP was changed from 25 µM (pH = 7.25) to 50 µM (pH = 6.25) in cardiac KATP channels (87). A similar shift was also observed in pancreatic KATP channels, presumably due to increases in ATPH3- and decrease in ATP4- by acidification (122). The latter form (-4 charge) of ATP could produce a more potent inhibition of the channel (122).

Phosphorylation by PKA or PKG stimulates vascular KATP channels, whereas PKC activation inhibits them (108). On the other hand, cardiac KATP channels were either stimulated by PKC (63) or primed for stimulation by metabolic inhibition or by pinacidil when PKC was activated (91). It was reported that PKC stimulated cardiac KATP channels at millimolar ATP and inhibited at micromolar ATP concentrations (<50 µM) (89). This resulted in a crossing (more shallow sigmoid curve) of the concentration-response curves for ATP inhibition when PKC activity was present (89).

    CHARACTERISTICS OF SINGLE KATP CHANNELS

In general, activities of KATP channels are not time dependent and exhibit little or no voltage dependence. The channels exhibit weak inward rectification on strong depolarization (see below). The opening of the channels appears in bursts, and flickering (brief openings and closings) within bursts decreases when the membrane is depolarized more strongly. Single-channel conductance of the KATP channel is ~80 pS in cardiac myocytes (71, 105, 115, 151, 154, 162) and 56-65 pS in pancreatic beta -cells (99, 127, 152), under conditions of symmetrical 140-150 mM K+. The IC50 values for ATP were almost similar in cardiac and pancreatic KATP channels (Table 2). However, there is controversy in VSM cells even as to the conductance of the KATP channel. This is probably partly due to the lower density of KATP channels (0.1-0.2 µm2) in VSM cells (108, 158) compared with that of cardiac tissue (1-10 µm2) (111, 116), which makes it difficult to identify these channels and to study their properties.

Large-conductance (100-258 pS) KATP channels were reported in VSM cells from rabbit mesenteric artery (95, 140) and rat tail artery (47). However, ATP also inhibited the large-conductance Ca2+-activated K+ (KCa) channels in VSM cells from porcine coronary artery (77, 133). Therefore, it was proposed by Edwards and Weston (38) that the large-conductance channels studied may actually have been KCa channels. One complication is that there might be multiple isoforms of the channel and/or multiple conductance levels (108) because two patterns of behavior of the KATP channels have been observed in rat portal vein myocytes (166).

Several studies have demonstrated by single-channel recording that the conductance of KATP channels in VSM cells are small or intermediate (15-50 pS) (12, 13, 25, 26, 70, 83, 163, 165, 166). These relatively small-conductance K+ channels were inhibited by glibenclamide and were activated by KCOs and MgNDP; they could be evoked under the conditions of severe hypoxia (26) or metabolic inhibition (12, 165). These characteristics of the K+ channels are closely similar to KATP channels in cardiac or pancreatic beta -cells. However, MgNDP, instead of ATP, seemed to be a more important regulator of a 20- to 26-pS K+ channel (12, 13, 163, 165) because 1) abrupt removal of ATP in inside-out patches did not produce any channel activity, 2) channel activation by KCOs usually required added MgNDP, and 3) MgNDP by itself stimulated the channels. Therefore, the authors referred to them as NDP-dependent K+ (KNDP) channels (12, 13, 165). However, in this review, these channels in VSM cells are designated as the KATP channel.

As mentioned above, one of the most surprising features of KATP channels in freshly isolated VSM cells is that no distinct channel activity appeared when inside-out patches were formed in ATP-free solution (70, 163, 165, 166). In addition, there are only a few studies that directly show channel inhibition by ATP (70, 166). Kajioka et al. (70) reported that the IC50 value was 29 µM for the effect of ATP on the KATP channel activity, which was obtained only in the presence of both pinacidil and MgGDP. On the other hand, Zhang and Bolton (166) demonstrated that the activity of similar channels in VSM cells was dose dependently activated by 0.1-1 mM ATP and was inhibited by increasing the ATP concentration to 3-5 mM, thus making a bell-shaped dose-response relationship (Table 2).

    A COMPLEX OF SUR AND KIR CONSTITUTES THE KATP CHANNEL

Electrophysiological properties of native KATP channels suggested that they are members of the inward-rectifying class of K+ channels. That is, amplitude of the outward current evoked by potentials more positive than EK was smaller than that of the inward current evoked by negative potentials. Since the cloning of Kir channels in 1993 [Kir1.1 (61), Kir2.1 (82), Kir3.1 (27)], several members of Kir channels have been identified and named as Kir subfamilies (Kir1.0-6.0), based on a unifying nomenclature (19). Hydrophobicity plots of cloned Kir channels predict a minimal structure, with only a "pore" region and two flanking membrane-spanning segments, M1 and M2 (Fig. 2A). Like voltage-dependent K+ channels, native inward-rectifying K+ channels are assumed to be tetramers formed from either the homometric or heterometric assembly of monomers (32, 113, 130).

Expression of Kir1.1 (ROMK1) channels in Xenopus oocytes revealed that MgATP was required for their activation, which suggested some similarity to native KATP channels in terms of the hydrolysis-dependent action of ATP (61) (Tables 1 and 3). However, the conductance of this channel was relatively small (31 pS), and the tissue distribution was mainly restricted to kidney. Kir3.4 channels expressed in mammalian cell lines were inhibited by ATP and were stimulated by both UDP and pinacidil, but glibenclamide had no effect on channel activity (11). This clone was initially called rcK<SUB>ATP<SUP>−1</SUP></SUB> (11), but the authors later proposed that they might have been measuring an intrinsic channel activity in the transfected cells rather than the activity of newly induced channels (11a). A later study provided compelling evidence that the heterometric assembly of Kir3.4 (CIR) and Kir3.1 (GIRK1) forms muscarinic (or acetylcholine)-activated K+ channels (79). A channel subunit of a new subfamily (Kir6.0) was recently identified and designated as Kir6.1 (67). Although the Kir6.1 channel was sensitive to ATP, its activity was weak and only slightly stimulated by diazoxide but was not inhibited by glibenclamide. However, the measured channels in this study (67) might also have been intrinsic to the transfected cells, and Kir6.1 itself may not form a functional K+ channel, as in the case for Kir6.2 (65, 129).

                              
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Table 3.   Identification of Kir channels and SURs related to KATP channels

Cloning of the regulatory protein that contains the SU-binding site has provided great advances in our understanding of the KATP channels (1, 66, 68, 148). The cloned protein, reported in 1995 (1, 148), was designated as the SUR. The SUR cDNA sequence encodes a protein of 1582 amino acids with a molecular mass of 177 kDa. The SUR contains two nucleotide-binding folds (NBFs) on the cytoplasmic side. The NH2 terminus is on the external face of the membrane, and it connects to two domains presumably composed of nine and four transmembrane-spanning helices, respectively (Fig. 2A). The latter domain separates the two NBFs (Fig. 2A). Accumulating evidence suggests that the native KATP channel is a complex of the two subunits, i.e., SUR and Kir channel (Fig. 2A). Clement et al. (21) have shown that the KATP channel is heteromultimeric, with a [(SUR/Kir6.x) × 4 (tetrameric)] stoichiometry (in which 6.x can be either 6.1 or 6.2). The first cloned SUR is now called SUR1 because two different isoforms (SUR2A and SUR2B) have recently been identified (20, 66, 68). SUR2A, discovered in mouse, has an almost identical sequence to that of SUR2. On the basis of the tissue distribution and expression experiments, SUR1, SUR2A, and SUR2B are assumed to be pancreatic, cardiac, and (vascular) smooth muscle types, respectively (Tables 3 and 4, see below).

                              
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Table 4.   KATP channels: complex of Kir channels and SURs

Simultaneous expression of both Kir6.2 and SUR1 exhibited KATP channel activity, whereas either component alone did not (65, 129). The expressed channel had a conductance of ~70 pS, was inhibited by ATP (IC50 = ~10 µM) and SU compounds [glibenclamide and tolbutamide (IC50 = 4.5 µM)], and was stimulated by diazoxide and pinacidil but not by cromakalim (54, 65, 129). These properties of the SUR1/Kir6.2 channel are closely similar to those of pancreatic KATP channels (Tables 2 and 4).

Because mRNA of SUR1 was absent, or expressed at low levels in rat heart (65), another isoform must be present in the cardiac KATP channel. SUR2A, which has 68% identity of amino acids with SUR1, is expressed at high levels in rat and mouse hearts but, in pancreas, only at moderate (rat) or zero (mouse) levels (66, 68). Coexpression of SUR2A and Kir6.2 forms a ~80-pS KATP channel that resembles that found in cardiac tissue (66). ATP inhibited the channel activity with an IC50 value of ~100 µM. Single-channel activity and 86Rb+ efflux (induced by metabolic poisoning) were inhibited by glibenclamide but with less sensitivity compared with pancreatic-type KATP channel (i.e., SUR1/Kir6.2). The SUR2A/Kir6.2 channel was stimulated by pinacidil and cromakalim but was not affected by diazoxide. These pharmacological data, conductances, and tissue distributions suggest that the cardiac KATP channel may be composed of SUR2A and Kir6.2 (Tables 2-4).

The actions of KCOs on pancreatic (SUR1/Kir6.2) and cardiac (SUR2A/Kir6.2) KATP channels (Table 4) are different compared with those on the native KATP channel in VSM cells (Table 2). The latter could be stimulated by pinacidil, cromakalim, and diazoxide (with less potency in diazoxide). Coexpression of the newly identified isoform, SUR2B, with Kir6.2 or Kir 6.1 conferred the same KCO sensitivity as that in VSM, that is, the channels were stimulated by all three agents, i.e., pinacidil, cromakalim, and diazoxide (68, 159) (Table 4). SUR2B, a protein of 1546 amino acid residues, has 97% identity with SUR2A (cardiac type) but only 67% identity with SUR1 (pancreatic type). The nonidentical part of SUR2B (42 amino acids) is located in the COOH-terminal end. However, this portion is highly homologous to that of SUR1, suggesting that it may be required for diazoxide activation of KATP channels (68).

The SUR2B/Kir6.1 channel was similar to the KATP channel in VSM cells [i.e., KNDP channel (12, 13, 165)], especially in terms of single-channel conductance and ATP sensitivity (159). For example, the relatively small conductance (33 pS) and the bell-shaped relation for ATP action on the channel (159) were closely related to those of VSM (Tables 2 and 4). That is, the channel was dose dependently stimulated by lower doses of ATP (0.1-100 µM), whereas it was inhibited by higher doses (1-3 mM) in the presence of pinacidil. The stimulatory effect at low doses required Mg2+ and so might be mediated through the NDP-binding stimulatory site.

In pancreatic or cardiac KATP channels, vigorous channel opening usually could be observed when inside-out patches were formed in ATP-free solution, whereas channel activity appeared in neither the SUR2B/Kir6.1-reconstituted channel nor native KATP channels expressed in VSM cells (Table 2). In the SUR2B/Kir6.1 channel and in the native KATP channel of VSM cells (i.e., KNDP channel), the channels required added NDPs or nucleotide triphosphates for proper function (12, 13, 70, 163, 165). The ubiquitous tissue distribution of both SUR2B and Kir6.1, including in smooth muscles (Table 3), also supports the idea that the KATP channel in VSM is a complex of SUR2B and Kir6.1. Thus the different ATP sensitivity of native VSM KATP channels (compared with that of pancreas and heart) might result from the distinct intrinsic property of the Kir channel subunit, as well as from the different isoforms of SUR (see below).

It has been suggested that the KATP channel may sense MgADP (NDP) through the two NBFs of the SUR subunit. Individuals affected with familial persistent hyperinsulinemic hypoglycemia of infancy have mutations of the SUR gene, which encodes for the two NBFs (NBF-1 and NBF-2) (36, 148, 149). In addition, coexpression of Kir6.2 and SUR1 having a point mutation of NBF-2 generated KATP channels that could be slightly stimulated by diazoxide but not opened in response to metabolic inhibition. Inside-out patch experiments revealed that the mutated channels had normal ATP sensitivity but were not stimulated by MgADP. In contrast, an equivalent point mutation in NBF-1 showed normal sensitivity to both MgADP and ATP (114). In a later study, mutations of the lysine residue in either NBF-1 or NBF-2 resulted in lack of stimulation by MgADP but normal ATP sensitivity (55). Thus MgADP (probably MgNDPs) stimulation of native KATP channels may be mediated through the NBFs.

Requirement of SUR for stimulation by KCOs has also been emphasized (3, 54, 55). Diazoxide stimulated the SUR1/Kir6.1 and the SUR1/Kir6.2 channels (both of which were sensitive to ATP and tolbutamide) but did not stimulate the Kir6.1 channel without SUR. Furthermore, NBFs (especially NBF-1) of SUR1 were essential for diazoxide stimulation of the SUR1/Kir6.2 channel (55). Therefore, it has been suggested that SUR1 is required to confer diazoxide sensitivity on the channel.

It is not fully known whether the ATP-sensing mechanism is mediated through the SUR or the Kir channel subunit itself. The answer to this question has been hampered by the fact that Kir6.2 channel subunit is not a functional K+ channel when expressed by itself. However, Tucker et al. (153) demonstrated that truncation of the COOH terminus of Kir6.2 allowed KATP channel activity in the absence of SUR. Truncation of Kir6.2, in either the last 26 or 36 amino acids of the COOH terminus (Kir6.2Delta C26, Kir6.2Delta C36), allowed expression of a functional channel whose IC50 values for ATP were 106 and 128 µM, respectively. [This is in contrast to the "ball-and-chain" hypothesis, as developed for voltage-gated K+ channels (62, 120), which proposes that the NH2 terminus of the channel may act as a blocking particle, plugging the pore and thereby inactivating the channel.] Coexpression of SUR1 not only endowed both diazoxide and tolbutamide sensitivities to the truncated channels but also enhanced the inhibitory action of ATP: the IC50 value was 13.4 µM in the SUR1/Kir6.2Delta C26 channel and 24.6 µM in the SUR1/Kir6.2Delta C36 channel. In addition, coexpression of SUR1 reduced the basal whole cell current (compared with the truncated channel alone) as if SUR1 acted as an inhibitory regulatory protein (Ri). The authors (153) suggested that the enhancement of ATP inhibition produced by SUR1 might be attributed to facilitated access of ATP to its inhibitory site on Kir6.2 because SUR is a member of the ATP-binding cassette transporter/channel superfamily (60). Therefore, the last 26 amino acids of Kir6.2 prevent its functional expression alone as a KATP channel, and this effect is prevented by SUR1.

    PROPOSED MODELS OF THE KATP CHANNELS IN CARDIAC AND VSM CELLS

As mentioned above, recent reports suggest that SUR endows the KATP channel with the stimulatory effects produced by MgADP and KCOs, as well as the channel inhibition produced by SU compounds; inhibition by ATP would be ascribed to the intrinsic property of the pore-forming subunit, i.e., Kir. Representations of the proposed models of KATP channels are depicted for cardiac cells (Fig. 2B) and VSM cells (Fig. 2C). Some parts of this model are based on those proposed by Terzic et al. (144), Tung and Kurachi (154), and Edwards and Weston (38). In this model, there are two functional gates, that is, A gate and N gate. In normal cardiac tissues, where ATP is present, the A gate is closed because the ATP-binding site on the Kir channel subunit (AK) is occupied by ATP. Affinity of the AK site for ADP is lower. If ATP is bound to both the ATP-binding site (AS) on the Ri (SUR) and the AK site (on Kir), this results in enhanced ATP sensitivity of the KATP channel. This is because the Ri 1) may facilitate access of ATP to the AK site and 2) unmasks the ATP sensitivity of the Kir channel subunit (153). The NDP-binding site (N site) is occupied by ADP, and it opens the N gate. In addition, phosphorylation of the run-down site (R site) helps to keep the N gate open. In other words, the N gate stays open either by NDP binding or by phosphorylation of R site because it has been shown that NDP binding produces effects similar to channel phosphorylation (154). The phosphorylation of the R site may also represent a maintenance action on the channel associated with hydrolysis of MgATP. When the SU-binding (S) site of Ri is occupied, the A gate becomes closed (Fig. 2B). In contrast, in some VSM tissues under physiological conditions (high ATP), it is likely that the KATP channel (i.e., KNDP channel) is active (i.e., A gate is open) (Fig. 2C), because the channel showed only weak inhibition by ATP in isolated patches and was strongly dependent on MgNDPs (i.e., ADP, GDP, and UDP) (see also above). The basal activity of the KATP channel in VSM cells might be due to 1) reduced ATP sensitivity of the Kir channel subunit, 2) attenuated ability of Ri to enhance ATP sensitivity of the AK site, 3) reduced action of Ri to unmask the ATP sensitivity of the Kir channel subunit, and 4) the strong stimulatory effect of NDP binding to the N site. Therefore, in this model of the VSM KATP channel, both A gate and N gate are open under normal condition (Fig. 2C).

    MOLECULAR INTERACTION BETWEEN SUR AND KIR CHANNEL SUBUNIT AND ROLE OF CYTOSKELETON

It is still not known how SUR and Kir work together as a functional KATP channel. Several studies provide possible mechanisms of the molecular connection between SUR and Kir subunit. For example, proteolysis by trypsin enhanced activities of both voltage-gated Ca2+ and K+ channels, probably due to removal of the rapid inactivation mechanism (59, 62). Similarly, treatment of cardiac or pancreatic KATP channels with trypsin (in isolated patches) potentiated channel activity (31, 48, 112, 121), as if it removed a tonic inhibition by an unknown regulatory protein. In addition, trypsin treatment markedly attenuated the regulatory mechanisms, including stimulation by MgADP (31, 121) and cromakalim (31) and inhibition by SU compounds (31, 112, 121). However, ATP sensitivity of the channel was only slightly reduced (31, 121) or was not affected (48). These results suggest that the trypsin treatment of the internal surface of the KATP channels might alter the molecular coupling between the SUR and Kir subunits. It was also reported that inhibition by SU compounds was attenuated by several factors, such as acidosis (44) and metabolic poisoning (2, 45, 80, 155), which might affect the molecular coupling.

It was suggested that stimulations of the KATP channel by MgADP and diazoxide, as well as inhibition by tolbutamide, require unknown cytosolic components because these effects were attenuated with time in excised patches (9, 85). This implies that such constituents may serve as a functional link between the SUR and Kir subunits.

It has been reported that the functions of many ion channels and transporters are modulated by the cytoskeleton (146). For example, it was reported that, in cardiac KATP channels, two different actin microfilament disrupters, deoxyribonuclease I and cytochalasin, stimulated the opening of the KATP channels (50, 145, 161). This suggested that the molecular connections between the actin filaments (located just underneath the cell membrane) and the KATP channel might act to attenuate the activity of the channel, such that disruption of these connections removes the inhibition of channel activity. Furthermore, these treatments impaired the ability of SU compounds to inhibit the channels (18, 161). In this respect, the actin filament network and its related proteins might be involved in signal transduction between the Ri (which contains the SU-binding site) and the channel. For example, the disruption of actin filaments, which might have some connection with Ri directly or through a linking protein, could result in dissociation of Ri from the channel, thereby blocking the signal from Ri to the channel (Fig. 3). This possible mechanism may be supported by the findings that Na+ channels (139), Na+-K+-ATPase (109), and the Na+/Ca2+ exchanger (88) bind to the cytoskeleton protein ankyrin, which associates with the actin filament network through spectrin (15).


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Fig. 3.   Proposed diagram for regulation of coupling between Ri and KATP channel subunit by cytoskeleton. A: when the actin filament is intact, Ri stays in its normal position and acts to attenuate channel activity. Ri contains the SU-binding site. Addition of SU gives nearly complete block. B: disruption of actin filaments results in dissociation of Ri from the channel, thereby blocking modulation of channel activity.

    SUMMARY AND PERSPECTIVES
Top
Abstract
Introduction
Summary
References

This review focused on the actions of the major endogenous regulators and drugs, i.e., ATP, NDPs, SU compounds, and KCOs, on the KATP channels of pancreatic, cardiac, and VSM tissues. Basically, these major factors regulate the native KATP channels in the same direction. That is, ATP and SU compounds inhibit the channels, whereas MgNDP and KCOs stimulate them. In addition to the inhibitory action of ATP binding (ligand action), ATP exerts a hydrolysis-dependent action that is required to maintain channel activity. Despite the common actions, there are some distinct differences in properties among these native KATP channels. For example, in VSM cells, a bell-shaped dose-response relationship for the ATP effect was reported, although the IC50 values were similar in cardiac and pancreatic KATP channels. Diazoxide, a prototype KCO, exerts a potent action on the pancreatic channel but does not stimulate the cardiac channel. Furthermore, the conductance of the channels and the sensitivity to inhibition by SU compounds are also different among these native channels (see Table 2).

Recent molecular biology and electrophysiological studies suggest that the KATP channel is composed of two proteins [i.e., SUR1/Kir6.2 (pancreatic), SUR2A/Kir6.2 (cardiac), and SUR2B/Kir6.1 (VSM)]. The Kir subunit consists of a pore region and two flanking membrane-spanning segments (Fig. 2A). The SUR contains two NBFs on the cytoplasmic side and is classified as the ATP-binding cassette transporter/channel superfamily. The SUR seems to endow the MgADP and KCO sensitivity to the channel, as well as the SU inhibition. The Kir6.0 subfamily itself may possess ATP sensitivity as an intrinsic property that can be unmasked or stimulated by coexpression with SUR. The SUR subunit may facilitate the access of ATP to the ATP-binding site on the Kir channel subunit. However, the mechanism of molecular interactions between SUR and Kir6.0 subfamily remains to be elucidated. Future studies will provide useful information and facilitate treatment of diseased states such as diabetes, myocardial ischemia, and hypertension.

    ACKNOWLEDGEMENTS

H. Yokoshiki thanks Prof. Akira Kitabatake (Hokkaido University, Sapporo, Japan) and Prof. Morio Kanno (Hokkaido University) for providing an opportunity to conduct joint research at the University of Cincinnati. The authors also acknowledge helpful comments on this manuscript by Dr. Andre Terzic (Mayo Clinic).

    FOOTNOTES

Address for reprint requests: H. Yokoshiki, Dept. of Molecular and Cellular Physiology, College of Medicine, Univ. of Cincinnati, 231 Bethesda Ave., PO Box 670576, Cincinnati, OH 45267-0576.

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