Phosphotransfer reactions in the regulation of ATP-sensitive K⁺ channels

^a Division of Cardiovascular Diseases, Departments of Medicine and Pharmacology, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA

	ABSTRACT

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ATP-sensitive K⁺ (K_ATP) channels are nucleotide-gated channels that couple the metabolic status of a cell with membrane excitability and regulate a number of cellular functions, including hormone secretion and cardioprotection. Although intracellular ATP is the endogenous inhibitor of K_ATP channels and ADP serves as the channel activator, it is still a matter of debate whether changes in the intracellular concentrations of ATP, ADP, and/or in the ATP/ADP ratio could account for the transition from the ATP-liganded to the ADP-liganded channel state. Here, we overview evidence for the role of cellular phosphotransfer cascades in the regulation of K_ATP channels. The microenvironment of the K_ATP channel harbors several phosphotransfer enzymes, including adenylate, creatine, and pyruvate kinases, as well as other glycolytic enzymes that are able to transfer phosphoryls between ATP and ADP in the absence of major changes in cytosolic levels of adenine nucleotides. These phosphotransfer reactions are governed by the metabolic status of a cell, and their phosphotransfer rate closely correlates with K_ATP channel activity. Adenylate kinase catalysis accelerates the transition from ATP to ADP, leading to K_ATP channel opening, while phosphotransfers driven by creatine and pyruvate kinases promote ADP to ATP transition and channel closure. Thus, through delivery and removal of adenine nucleotides at the channel site, phosphotransfer reactions could regulate ATP/ADP balance in the immediate vicinity of the channel and thereby the probability of K_ATP channel opening. In this way, phosphotransfer reactions could provide a transduction mechanism coupling cellular metabolic signals with K_ATP channel-associated functions.—Dzeja P. P., Terzic, A. Phosphotransfer reactions in the regulation of ATP-sensitive K⁺ channels. FASEB J. 12, 523–529 (1998)

Key Words: K_ATP channel • adenylate kinase • creatine kinase • pyruvate kinase • glycolysis • metabolic signaling

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PHOSPHOTRANSFER SYSTEMS:... TRANSITION OF ATP TO... TRANSITION OF ADP TO... INTEGRATIVE PHOSPHOTRANSFER... SUMMARY REFERENCES

 
PRESENT THROUGHOUT the body, ATP-sensitive K⁺ (K_ATP)² channels transduce cellular metabolic signals into membrane potential changes and regulate cellular functions as diverse as hormone secretion in the pancreatic ß-cell and cardioprotection in the myocardium (1–6). The endogenous inhibitor of K_ATP channels is intracellular ATP, and ADP serves as the channel activator (1–9). K_ATP channels are heteromultimers formed by association of an inwardly rectifying K⁺ channel, Kir6.2, and an ATP binding cassette (ABC) known as the sulfonylurea receptor (SUR) (5, 6, 10–19). Kir6.2 and SUR are believed to be responsible for the ATP-induced inhibition of channel opening, whereas SUR, which possesses two cytosolic nucleotide binding folds, is also responsible for ADP-induced activation of K_ATP channels (5, 6, 8, 9, 16, 20) ( Fig. 1 and Fig. 2). Although the defining property of K_ATP channels is their nucleotide-dependent gating (1–9, 20–24), it is still unresolved how transition occurs from the ATP- to the ADP-liganded channel state in an environment of millimolar concentrations of intracellular ATP.

View larger version (38K): [in this window] [in a new window]   Figure 1. The adenylate kinase (AK) phosphotransfer system and regulation of KATP channel opening. ADP generated by ATPases serves as a substrate to drive AK-catalyzed reactions to form AMP. In addition, AMP can be produced by other AMP-generating reactions present within a cell. AMP molecules are delivered to the KATP channel site through the AK-catalyzed phosphotransfer system (38, 44). AK converts AMP to ADP in the microenvironment of the channel, and in the process uses ATP bound to or present in the vicinity of KATP channel subunits, leading to channel opening. AK is active under conditions when creatine kinase, oxidative phosphorylation, and/or glycolytic systems are suppressed, as it occurs in muscle cells during metabolic stress or in the absence of a glucose challenge in pancreatic ß-cells. Stimulation of the creatine kinase or the pyruvate kinase/glycolytic systems, which are thermodynamically more favorable than AK, suppresses the AK-catalyzed generation of AMP and could thereby promote KATP channel closure (see Fig. 2). Abbreviations: 6.2, Kir6.2 inward rectifier K+ channel; SUR, sulfonylurea receptor (a regulatory subunit of the KATP channel); AK, adenylate kinase.

View larger version (42K): [in this window] [in a new window]   Figure 2. The creatine kinase (CK) and glycolytic phosphotransfer systems and the regulation of KATP channel closure. The CK system provides a link between ATP-generating and ATP-utilizing or -sensing cellular sites. The glycolytic system could also provide a similar intracellular energy transfer pathway (44) by transferring mitochondria-produced, high-energy phosphoryls through hexokinase/glucokinase, phosphofructokinase, and the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase couple present in the vicinity or bound to the mitochondrial outer membrane, as well as by generating additional ATP molecules as a product of glycolytic reactions. Activation of the CK and pyruvate kinase/glycolytic systems promotes removal of ADP from the KATP channel site and increases the rate of delivery of ATP to channel subunits. Reversal from the ADP-liganded to the ATP-liganded channel state leads to KATP channel closure.

Cytosolic levels of ATP exceed the concentrations required to keep the channel closed even under conditions known to affect K_ATP channel activity such as glucose challenge in pancreatic ß cells or moderate hypoxia in the myocardium (25–28). Millimolar concentrations of intracellular ATP would saturate the ATP binding site (or sites) on the K_ATP channel complex, keeping the channel closed (1–6, 11, 12, 20, 21). In fact, regardless of the metabolic state of a living cell, the cytosolic concentrations of ATP are one to two orders of magnitude higher than the apparent IC₅₀ value required for ATP-induced channel inhibition (1, 2, 21, 27).

Although some reports indicate that an increase in ATP accompanied by an increase in total adenine nucleotide content (29) can be found in cellular extracts from pancreatic ß-cells exposed to high glucose, and that in ventricular extracts from hearts exposed to severe and prolonged hypoxia, cytosolic levels of ATP can drop (30), the time course and magnitude of such changes do not necessarily correlate with the dynamics of K_ATP channel activity (1, 2, 21, 27). In parallel, cellular free ADP levels may be reduced from 35 to 20 µmol/l after switching ß-cells from a low to a high glucose medium (25) or may increase moderately in heart muscle under hypoxia (27, 28, 30). However, it has not been established whether such changes in cytosolic ADP in the presence of millimolar levels of ATP are sufficient to account for the regulation of K_ATP channel activity (1, 2, 21, 27, 30). Some reports indicate that changes in the intracellular ATP/ADP ratio, a more sensitive index of fluctuations in the intracellular concentration of adenine nucleotides, are sufficient to cause change in K_ATP channel activity, particularly in cells previously deprived of nutrients (29, 31–33). However, in other studies conducted under less drastic conditions, such changes were not readily detectable and did not correlate with changes in K_ATP channel activity (2, 21, 27, 34–36).

Recently, the existence of intracellular phosphotransfer networks able to transfer phosphoryls between different cellular compartments in the absence of major changes in cytosolic levels of adenine nucleotides or changes in the ATP/ADP ratio has been established (37–39). In light of these findings, transitions between the ATP- (closed) and ADP-liganded (open) K_ATP channel states could be accomplished through reversible phosphotransfers between ATP and ADP molecules. The microenvironment of the K_ATP channel apparently harbors phosphotransfer enzymes with phosphotransfer rates that closely correlate with K_ATP channel activity and associated cellular functions. The present overview summarizes recent evidence for the participation of intracellular phosphotransfer reactions in the regulation of K_ATP channels.

	PHOSPHOTRANSFER SYSTEMS: IMPORTANCE OF ADENYLATE KINASE

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A number of phosphotransfer systems participate in various cellular energy transfer and signaling pathways (37–41). Phosphotransfer reactions catalyzed by adenylate kinase in conjunction with creatine kinase, as well as pyruvate kinase and other glycolytic enzymes, have been implicated in the regulation of K_ATP channels (36, 42–44). The properties and physiological significance of phosphotransfers catalyzed by creatine kinase, as well as pyruvate kinase and other glycolytic enzymes, have been described previously (21, 37, 42).

Adenylate kinase (AK) catalyzes reversible phosphotransfer between ADP and ATP in the presence of AMP and has been implicated in the processing of cellular signals associated with ATP utilization (45–47). Isoforms of this enzyme have been found in mitochondria and cytosol or are membrane bound (43, 45, 48). The spatial arrangement of AK provides a bidirectional, thermodynamically efficient phosphorelay that links ATP-generating with ATP-consuming or -sensing cellular processes (38, 44, 49, 50). It has been established both in muscle and pancreatic ß-cells that AK-catalyzed reactions possess a high degree of fidelity to the magnitude, onset, and duration of the cellular metabolic response (36, 38, 50).

Impaired AK activity leads to disturbances in cellular functions. Deficiency of the cytosolic and membrane-bound AK1 isoform has major consequences, including mental retardation associated with congenital hemolytic anemia (51), whereas reduction in the activity of the mitochondrial AK3 isoform has been observed in the ischemia-injured myocardium (52). Mutations in the AK gene have been linked to loss of osmoprotection conferred by the ProU transporter, a member of the ABC superfamily (53).

Certain members of the ABC superfamily possess AK-like activity, as is the case with nucleotide binding folds of the cystic fibrosis conductance regulator (CFTR) (54). Selective ligands of AK can modulate the activity of CFTR (55) as well as the activity of certain ion conductances such as the Ca²⁺-activated K⁺ channel (56). AK activity has not been reported so far within the K_ATP channel complex. However, membrane-associated AK activity has been found in cells that express a high density of K_ATP channels, such as the sarcolemma of cardiac cells (43). Such AK-catalyzed activity could, in principle, participate in phosphotransfer regulation in the vicinity of K_ATP channels.

	TRANSITION OF ATP TO ADP AND CHANNEL OPENING

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Available data suggest that transition from the ATP- to the ADP-liganded state of the K_ATP channel and channel opening could be mediated, at least in part, through phosphotransfer catalyzed by a membrane-associated AK activity found in the vicinity of the channel (43). In excised membrane patches, AMP, the substrate of AK, promotes opening of ATP-inhibited pancreatic and cardiac K_ATP channels (43, 57). This effect is prevented by inhibitors of AK (43). Purified AK applied to the intracellular milieu of cardiac cells can also promote K_ATP channel opening (43), whereas selective inhibitory ligands of AK reduce its probability of occurring (58–60). In intact cells, net AK-catalyzed phosphotransfer flux closely correlates with K_ATP channel-associated functions (36, 43, 44). Reduction in AK-catalyzed metabolic flux is associated with cellular functions such as insulin secretion in pancreatic ß-cells, which depend on K_ATP channel closure (36). Together, these findings suggest a role for AK in regulating K_ATP channel behavior.

Transitions from the ATP- to the ADP-liganded state of the K_ATP channel could also be catalyzed by an ATPase activity inherent to the K_ATP channel components. In this regard, it has been established that certain members of the ABC superfamily, including membrane transporters such as CFTR, possess ATPase-like activity (54, 61). However, such activity has so far not been reported within the K_ATP channel complex (6).

The AK-catalyzed reversal of the ATP-liganded state can occur in an environment of high and constant intracellular concentrations of ATP (43, 44, 57). This is possible because AK activity at the K_ATP channel site is connected with the intracellular AK phosphotransfer reaction network that couples remote ATP-generating processes with ATP-utilizing or ATP-sensing cellular components (38, 44) ( Fig. 1). Studies of metabolic dynamics in intact cells making use of oxygen-18 and ³¹P nuclear magnetic resonance-based techniques indicate that such integration could be achieved by sequential and concurrent phosphotransfers along the chain of AK enzymes ( Fig. 1), which operate in parallel with creatine kinase (CK) -catalyzed ( Fig. 2) phosphotransfer reactions (37, 38, 44, 49). These phosphotransfer chains form a relay, resulting in the propagation of metabolic flux and a spatially directed conduction of ligands (37, 44). At an ATP utilization (ATPase) site distal to the K_ATP channel, AMP is generated from ADP by AK-mediated catalysis ( Fig. 1). The rate of AMP generation, in turn, determines the frequency at which AMP will be transmitted to the site proximal to the K_ATP channel, where it will undergo AK-catalyzed phosphorylation by ATP into ADP ( Fig. 1). Thus, AMP represents the pivotal signaling ligand driving the dynamic chain of sequential AK-catalyzed reactions (44). Such an AMP signaling mechanism has a large amplification potential. With each AK-mediated catalytic cycle, which uses one molecule of AMP as a reactant, one `inhibitory' molecule of ATP is removed from the channel site and two `activator' molecules of ADP are generated ( Fig. 1).

Changes in the levels of AMP and AK-catalyzed phosphotransfer occur in intact cells under conditions such as myocardial ischemia that are known to affect K_ATP channel activity (28). In conjunction with AK, the source of AMP can be provided by various cellular ATPases and processes that generate AMP, including fatty and amino acid activation reactions (38). Indeed, several reports indicate a tight functional link between plasmalemmal Na,K-ATPases and K_ATP channels (21, 62, 63). Moreover, the arrhythmogenic effect of free fatty acids observed in hypoxic cardiac cells could be associated in part with an increased rate of AMP generation, resulting in an enhanced probability for K_ATP channel opening and altered repolarization of the cardiac action potential (64). Also, an antagonistic relationship has been reported between fatty acid and glucose oxidation with regard to insulin secretion and associated K_ATP channel closure (65). Thus, AMP could serve a role in intracellular metabolic signaling through regulation of AK-mediated phosphotransfer, as well as associated glycolysis and oxidative phosphorylation, ultimately leading to regulation of K_ATP channel activity (36, 43, 44, 49). Within the microenvironment of K_ATP channels, this appears to be accomplished by an AMP-driven catalytic transformation of ATP into ADP, whose rate is suggested to be governed by the frequency of AMP delivery from cellular AMP-generating sites to the channel site (44).

	TRANSITION OF ADP TO ATP AND CHANNEL CLOSURE

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Transition from the ADP-liganded back to the ATP-liganded state would lead to K_ATP channel closure. Simple diffusional exchange of protein-bound nucleotides, as is the case with the transition in G-proteins from the GDP- to the GTP-liganded state and also within certain members of the family of ABC proteins, has been characterized (54, 61, 66). It is a rather slow process, however, in contrast to fast phosphotransfer reactions, which could assure rapid switching between the liganded-states of nucleotide-gated proteins. Along with AK, phosphotransfer reactions catalyzed by creatine and pyruvate (PK) kinases have been found in the vicinity of K_ATP channels and are implicated in the regulation of K_ATP channel activity (21, 42). In this regard, K_ATP channels would differ from other inwardly rectifying K⁺ channels, such as the muscarinic-operated K⁺ channel, whose activity is supported by nucleoside diphosphate kinase, a different phosphotransfer enzyme (41).

The equilibrium of CK- and PK-catalyzed phosphotransfer reactions are shifted toward ATP production ( Fig. 2). Therefore, the activity of CK and PK may favor closure of K_ATP channels. In heart muscle, closure of K_ATP channels is induced by substrates of CK-and PK-catalyzed phosphotransfer reactions—namely, creatine phosphate and/or phosphoenolpyruvate (42, 67). A role for CK and glycolytic phosphotransfer reactions has also been proposed in pancreatic ß-cells (44, 68). CK and PK phosphotransfer reactions, present in the vicinity of K_ATP channels, are linked to other intracellular compartments through near-equilibrium networks catalyzed by a relay of CK and glycolytic enzymes. Therefore, the metabolic dynamics of substrates required for CK- and PK-mediated phosphotransfer, including creatine phosphate and glycolytic intermediates, may represent an important determinant of K_ATP channel activity (42, 68, 69).

In addition to serving as a transfer mechanism for high-energy phosphoryls, the glycolytic system may also transfer inorganic phosphate and NADH through the rapidly equilibrating couple of glyceraldehyde-3-phosphate dehydrogenase and 3-phosphoglycerate kinase (44). Such a property may also be important in regulating K_ATP channels, since in addition to nucleotide-dependent gating, K_ATP channel-dependent functions (including insulin release) are modulated by the intracellular dynamics of inorganic phosphate and NADH (25, 26).

	INTEGRATIVE PHOSPHOTRANSFER SYSTEMS AND REGULATION OF KATP CHANNEL BEHAVIOR

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Concurrent actions of AK, CK, and PK could contribute to regulation of the ATP-ADP exchange rates at the channel site and thereby modulate the equilibrium between the open and closed channel states. The AK-catalyzed phosphotransfer system would promote K_ATP channel opening primarily by accelerating conversion of ATP to ADP (36, 43, 57), whereas CK and PK/glycolytic systems would predominantly facilitate conversion of ADP to ATP and channel closure (42, 70) ( Fig. 1and Fig. 2). Such a dual outcome in the regulation of K_ATP channel activity may, in turn, permit rapid response and transduction of metabolic signals into membrane electrical events. The open–closed transition that governs K_ATP channel behavior would thus be regulated through competitive interactions between the AK system on the one hand and the CK/PK/glycolytic system on the other ( Fig. 1and Fig. 2).

Several observations illustrate the physiological importance of competitive interactions between AK and CK/glycolytic systems. In resting muscle, the velocity of AK-mediated catalysis is suppressed, leaving phosphoryls to be transferred through the CK, and possibly the glycolytic, systems associated with K_ATP channel closure (38, 44, 49). Under metabolic stress, inhibition of CK and/or glycolysis in intact muscle results in a marked increase in the rate of AK-catalyzed phosphotransfer (38, 44, 49). Also, metabolic poisons such as iodoacetate that inhibit both CK and glycolysis produce strong activation of K_ATP channels (42, 70, 71). In insulin-secreting pancreatic cells, an increased glycolytic and CK flux occurring in response to elevated extracellular glucose concentration results in suppression of the AK-catalyzed phosphotransfer, apparently by competition for ADP, a common substrate for both reactions (36, 44, 72). The intracellular ADP generated by ATPase reactions is commonly processed by either AK or CK and/or the glycolytic systems (61). Conversion of ADP by AK would result in AMP generation, which enhances the probability for K_ATP channel opening (43, 57). Conversely, CK and the PK/glycolytic systems could readily transform ADP into ATP, deliver it to the channel site, and thereby promote K_ATP channel closure (36, 44).

	SUMMARY

TOP ABSTRACT INTRODUCTION PHOSPHOTRANSFER SYSTEMS:... TRANSITION OF ATP TO... TRANSITION OF ADP TO... INTEGRATIVE PHOSPHOTRANSFER... SUMMARY REFERENCES

 
This synopsis summarizes recent findings regarding intracellular phosphotransfer cascades catalyzed by AK, CK, and PK/glycolytic enzymes and the possible role of these signaling relays in regulating K_ATP channel activity. Although the constitutive components of the K_ATP channel have been identified and the nucleotide-dependent channel gating established, the mechanism by which transition from the ATP- to the ADP-liganded channel state is achieved remains less certain. Recent data suggest that near-equilibrium phosphotransfer reactions may provide a means for regulation of the open–closed K_ATP channel transition. Such phosphotransfer systems, linking intracellular ATP-generating and ATP-consuming or ATP-sensing processes, may transfer both ATP and ADP to the channel site and promote nucleotide exchange within the microenvironment of channel components. This, in turn, would define the probability of K_ATP channel opening despite rather constant levels of intracellular adenine nucleotides.

	ACKNOWLEDGMENTS

 
We would like to acknowledge the long-standing contributions made by Dr. N. D. Goldberg (University of Minnesota) in the development of the concept of dynamic phosphoryl transfer reactions. Work in the authors' laboratory was supported by the Bruce and Ruth Rappaport Program in Vascular Biology and Gene Delivery, the Miami Heart Research Institute, the American Heart Association, and the National Institutes of Health (T32 HL 07111).

	FOOTNOTES

 
¹ Correspondence: Guggenheim 7, Mayo Clinic, Mayo Foundation, Rochester, MN 55905, USA. E-mail: terzic.andre{at}mayo.edu

² Abbreviations: 6.2, Kir6.2 inward rectifier K⁺ channel; SUR, sulfonylurea receptor (a regulatory subunit of the K_ATP channel); CK, creatine kinase; PK, pyruvate kinase; K_ATP, AT-sensitive K⁺; ABC, ATP binding cassette; AK, adenylate kinase; CFTR, cystic fibrosis conductance regulator.

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