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J Appl Physiol 103: 1888–1893, 2007; doi:10.1152/japplphysiol.00747.2007. Invited Review HIGHLIGHTED TOPIC Perspectives in Innate and Acquired Cardioprotection ATP-sensitive potassium channels: metabolic sensing and cardioprotection L. V. Zingman,1,2 A. E. Alekseev,2 D. M. Hodgson-Zingman,1 and A. Terzic2 1 University of Iowa, Carver College of Medicine, Iowa City, Iowa; and 2Mayo Clinic College of Medicine, Rochester, Minnesota homeostasis; energetics; heart failure; energetic signaling bodily homeostasis, facilitating delivery of oxygen and nutrients, while assisting with metabolic end-product removal. The cardiovascular system operates under a variety of demands, ranging from conditions of rest to extreme stress, the later requiring significant increase in the amount of blood that needs to be pumped. Even a minor mismatch between cardiac workload and organism needs can precipitate a fatal outcome (9, 20, 44). Heart muscle itself is a high-energy, demanding organ with ⬃2% of ATP content consumed with every beat, primarily supporting excitationcontraction coupling and force generation. Without proper adjustment of ATP production to match workload, energetic resources would be rapidly consumed (⬃15 s to 1 min, depends on heart rate), underscoring the energy dependence of the working myocardium (9, 44). How the heart muscle matches the rates of ATP production with utilization is an area of active investigation. Traditional models of feedback adjustment of ATP hydrolysis and synthesis, based simply on cytosolic levels of ADP and inorganic phosphate, are reevaluated, as no tight correlation between cardiac workload and changes in bulk adenine nucleotide or inorganic phosphate levels is readily demonstrable in vivo or THE HEART FUNCTIONS TO MAINTAIN Address for reprint requests and other correspondence: L. Zingman, Univ. of Iowa, Dept. of Internal Medicine, 285 Newton Rd., CBRB2296, Iowa City, IA 52242 (e-mail: [email protected]). 1888 in vitro (4, 9, 20, 44, 59). This creates an apparent paradox where, at maintained ATP concentrations, ATPases with a high affinity toward ATP would function virtually in an independent mode from energy stores. The explanation may lie in metabolic compartmentation, metabolic “channeling”, cooperative kinetics, or parallel regulation of ATP-producing and -consuming cellular systems (4, 9, 20, 31, 37, 44, 46, 53, 59). In this regard, metabolic sensors, exemplified by the ATP-sensitive potassium (KATP) channel, serve a critical role in the orchestration of cell well-being (4, 33, 47, 58, 59, 69, 76, 78). Formed as heteromultimers of inwardly-rectifying potassium K⫹ channel (Kir) 6.2 and ATP-binding cassette (ABC) sulfonylurea receptor (SUR) 2A proteins, myocardial KATP channels are unique channel-enzyme complexes that provide linkage between cellular energetics and membrane excitability (2– 4, 14, 26, 28 –30, 36, 43, 47, 54, 55, 58, 64, 70 –72, 75, 78). KATP channels are coupled with phosphotransfer reactions that, in cells in which the mobility of metabolites between intracellular microdomains is otherwise limited, integrate energetic signaling systems (1, 4, 10, 11, 13, 15, 18, 19, 25, 59, 75). Coupling of phosphotransfer pathways with KATP channels permits a high-fidelity translation of energy fluxes into channel gating, adjusting membrane excitability to match demand (1, 4, 13, 25, 33, 76). KATP channel-dependent modulation of cardiac action potential duration, in accord with the cellular energetic state, allows synchronized energy consumption and produc- 8750-7587/07 $8.00 Copyright © 2007 the American Physiological Society http://www. jap.org Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017 Zingman LV, Alekseev AE, Hodgson-Zingman DM, Terzic A. ATP-sensitive potassium channels: metabolic sensing and cardioprotection. J Appl Physiol 103: 1888 –1893, 2007. doi:10.1152/japplphysiol.00747.2007.—The cardiovascular system operates under a wide scale of demands, ranging from conditions of rest to extreme stress. How the heart muscle matches rates of ATP production with utilization is an area of active investigation. ATP-sensitive potassium (KATP) channels serve a critical role in the orchestration of myocardial energetic wellbeing. KATP channel heteromultimers consist of inwardly-rectifying K⫹ channel 6.2 and ATP-binding cassette sulfonylurea receptor 2A that translates local ATP/ ADP levels, set by ATPases and phosphotransfer reactions, to the channel pore function. In cells in which the mobility of metabolites between intracellular microdomains is limited, coupling of phosphotransfer pathways with KATP channels permits a high-fidelity transduction of nucleotide fluxes into changes in membrane excitability, matching energy demands with metabolic resources. This KATP channel-dependent optimization of cardiac action potential duration preserves cellular energy balance at varying workloads. Mutations of KATP channels result in disruption of the nucleotide signaling network and generate a stress-vulnerable phenotype with excessive susceptibility to injury, development of cardiomyopathy, and arrhythmia. Solving the mechanisms underlying the integration of KATP channels into the cellular energy network will advance the understanding of endogenous cardioprotection and the development of strategies for the management of cardiovascular injury and disease progression. Invited Review KATP CHANNELS: METABOLIC SENSING AND CARDIOPROTECTION Fig. 1. Schematic presentation of the ATP-sensitive potassium (KATP) channel’s role in the balance of cardiac ATP production and utilization. KATP channels couple cardiac energetic load (set by heart rate arterial pressure and action potential duration) and energy production through control of membrane excitability. The homeostatic role of the KATP channel function is particularly critical in conditions elevating cardiac workload: hypertension (HTN) and tachycardia (THC). J Appl Physiol • VOL pore closure or negative channel gating (75). Recruitment of a posthydrolytic MgADP-bound state promotes opening of ATPinhibited KATP channels or positive channel gating (75). Elevated levels of intracellular MgADP, as occurs under metabolic stress, effectively decelerate ATPase cycling, increasing the probability of the posthydrolytic conformation associated with channel opening. NBD2 ATPase catalysis is characterized by a relatively long lifetime of the NBD2䡠ADP intermediate state compared with shorter lifetimes in other intermediates, NBD2䡠ATP and NBD2䡠ADP䡠Pi (10, 11, 75). Thus the probability that NBD2 will adopt the ADP-bound state through the ATPase cycle will be higher than the probability that this state will form through simple competitive binding in the absence of ATPase activity (11, 59). An additional conformational rearrangement that transmits the information provided by catalytic intermediates of SUR to the channel pore may rely on the dimerization of the two NBDs, as recently established for a number of ABC proteins (4, 5, 24, 27, 61). In the KATP channel complex, cooperative interaction, rather than separate contributions of each of the NBDs in SUR2A, is critical for coupling NBD2 ATP intermediates and the functional state of the KATP channel pore (40 – 42, 68, 77). KATP channels operate in a compartmentalized milieu with diffusional restrictions. Intracellular bulk nucleotide levels have apparently only limited direct effect on KATP channels (59). The channel agonist, MgADP, even at saturating levels (⬎100 M), shifts the range for ATP-induced KATP channel inhibition to an IC50 from ⬃30 to ⬃300 M, which is below actual bulk intracellular ATP levels (6 –10 mM) and, therefore, cannot per se explain promotion of channel activity (59). However, several observations support the notion that energy consumption is compartmentalized in cardiac cells and that the free diffusional space within the cellular microenvironment is limited, thus restricting metabolite mobility (4, 31, 37, 59). Thereby, in the presence of local ATP-consuming systems, submembrane nucleotide concentrations will be distinct from average cytosolic levels (59). This would provide a possible explanation for the activity of KATP channels measured even in the absence of detectable gross changes in cytosolic ATP/ADP levels. Although the existence of diffusional barriers may explain KATP channel regulation by local nucleotide levels, their function as cellular energetic sensors, securing beneficial channel activity in accord with cellular energetic demand, requires a network mechanism that would shunt diffusional barriers, allowing cellular energetic signal transfer (18, 19, 46, 59). KATP channels: components of the cellular energetic network. Nucleotide exchange between the SUR2A ATPase and intracellular metabolic pathways provides a mechanism coupling KATP channel function with cellular energetics (10, 11, 75). Cardiomyocytes possess well-defined phosphotransfer systems that facilitate energetic signaling between sites of ATP production and ATP utilization or sensing (18, 19, 46, 50, 59). Structural and functional interactions of KATP channel proteins with the prototypic phosphotransfer enzymes, adenylate kinase (AK; 2ADP 7 ATP ⫹ AMP) and creatine kinase (CK; ADP ⫹ CrP 7 ATP ⫹ Cr), are assured by the distribution of these enzymes in distinct cellular compartments, including membranes, and their physical association with KATP channel subunits (1, 13, 18, 19). The high rate of the major phosphotransfer reaction, catalyzed by CK, scavenges ATPase products and 103 • NOVEMBER 2007 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017 tion, preserving cellular energy balance at different workloads (4, 76) (Fig. 1). Cardiac KATP channels: Kir6.2/SUR2A complexes. Abundant in metabolically active tissues, KATP channels were originally discovered in the heart sarcolemma (48). Tetramers of Kir6.2 comprise the pore of cardiac KATP channels (2, 14, 28, 36, 67). Yet pore-forming Kir6.2 subunits cannot readily traffic to the plasma membrane alone, without the regulatory SUR module, due to a COOH-terminal RKR endoplasmic reticulum retention signal (56, 57, 74). Truncated Kir6.2, lacking retention signals, can reach the plasma membrane-generating channels that only partially reconstitute properties of intact KATP channels (67). Both the NH2- and COOH-termini of Kir6.2 apparently contribute to recognition of ATP, the major inhibitory channel ligand, with two Kir6.2 subunits implicated in the coordination of one ATP molecule (6, 63, 66). Mutations that impact the ATP responsiveness of Kir6.2 alter cardiac mechanical properties at rest and produce a poor myocardial response to ischemic and metabolic challenge (51), while in noncardiac tissues they are associated with disease states characterized by deficient metabolic coupling (21). Assembly of Kir6.2 with SUR2A enhances ATP-induced channel inhibition. Furthermore, fundamental KATP channel properties, including stimulation by MgADP and potassium channel openers, as well as inhibition by sulfonylurea drugs that are absent in truncated Kir6.2 channels, are rescued by coexpression of Kir6.2 with the SUR protein (4, 7, 12, 16, 28 –30, 43, 45, 50, 52, 60, 64). SUR2A, the regulatory subunit of the cardiac KATP channel, incorporates two bundles of six hydrophobic transmembrane-spanning domains (TMD) that are fused to hydrophilic nucleotide binding domains (NBD), also known as the ABCs (2, 4, 5, 8, 35, 40 – 42, 75). By virtue of structure and sequence homology, SUR belongs to the ABCC subfamily of ABC proteins (http://www.gene.ucl.ac.uk/ nomenclature/genefamily/abc.html) that usually exist as dimers with two ABC modules and two TMDs (TMD-ABCTMD-ABC). SUR (TMD0-TMD-ABC-TMD-ABC) (4), in addition to its unique property of association with a distinct protein subunit, Kir6.2, also contains an additional bundle of five TMDs (TMD0), proposed to anchor SUR to the Kir6.2 channel pore (8). NBD2 of SUR, in the presence of Mg2⫹, hydrolyses ATP, while NBD1 is primarily responsible for nucleotide binding (10, 11, 22, 40 – 42, 68, 75, 77). The intrinsic SUR-mediated catalysis is involved in the regulation of Kir6.2 pore gating (10, 11, 75) (Fig. 2). The SUR ATPase trapped in the prehydrolytic MgATP-bound state translates into 1889 Invited Review 1890 KATP CHANNELS: METABOLIC SENSING AND CARDIOPROTECTION facilitates disengagement of posthydrolytic conformations, promoting SUR ATPase cycling (10, 11, 59, 75). As a consequence of metabolic stress, a drop of CK flux compromises ADP removal from ATPase sites and suspends the ATPase cycle in a MgADP-bound state, producing channel opening, a regulation absent in knockout mice lacking the major CK gene M-CK (1, 10, 75). Analogously, AMP, the substrate for AK, antagonizes ATP-induced KATP channel closure, an effect lost in cardiomyocytes from mice lacking the primary AK1 isoform (13). Thus phosphotransfer reactions are identified regulators of KATP channel activity, providing a mechanism for coupling channel behavior with the cellular energetic state. J Appl Physiol • VOL KATP channels and cardioprotection. Due to integration with the cellular energetic network, KATP channels adjust cardiomyocyte membrane excitability and produce shortening of the cardiac action potential duration, limiting intracellular calcium loading under conditions of increased demand and high-cardiac performance. KATP channel-dependent action potential shortening secures electrical stability and diastolic interval prolongation, preserving a systolic/ diastolic calcium differential that is optimal for cardiac relaxation and suppression of triggered arrhythmia secondary to calcium-dependent afterdepolarizations (23, 25, 32– 34, 38, 49, 58, 73, 76). 103 • NOVEMBER 2007 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017 Fig. 2. Mutations in the ABCC9-encoded regulatory channel subunit sulfonylurea receptor (SUR) 2A disrupt KATP channel integration with cellular energetic network. A: Lineweaver-Burk plot for nucleotide binding domain (NBD) 2 ATPase activities measured by spectrophotometry revealed a Vmax ⫽ 9.98 ⫾ 0.34 min⫺1 and Km ⫽ 0.11 ⫾ 0.02 mM, determined at 0 ADP plus creatine kinase (CK; 0.01 U/ml) and creatine phosphate (CrP; 5 mM). B: Lineweaver-Burk plot for ADP-dependent inhibition of the NBD2 ATPase revealed KADP ⫽ 8.6 ⫾ 0.3 M (5). C: CK (⫹ CrP) promotes ATP hydrolysis in a fusion NBD2-maltose binding protein (MBP) constructs. Generation of [32P]Pi by purified constructs from [␥-32P]ATP was analyzed by thin-layer chromatography, followed by autoradiography (10). D: rate-limiting steps in the SUR2A ATPase cycle are as follows: for wild-type (WT)-ADP dissociation (k4), for constructs repeating SUR2A human mutations associated with dilated cardiomyopathy/Fs1524-Pi dissociation (k3), and for A1513T-abnormally slow k4. In addition, A1513T displays the lowest k04 rate constant defining ADP association (11). E: ADP-scavenging by CK accelerates the ATPase in WT, but not in NBD2 mutants. F-G: Fs1524 and A1513T SUR2A mutants produced KATP channel phenotype characterized by reduced ATP sensitivity and blunted response to ADP relative to KATP channel activity at zero nucleotide levels. [Adapted from Refs. 11 and 75.] Invited Review KATP CHANNELS: METABOLIC SENSING AND CARDIOPROTECTION J Appl Physiol • VOL missense and frame-shift mutations were mapped to domains bordering the catalytic ATPase pocket within SUR2A. Mutant SUR2A proteins reduced the intrinsic channel ATPase activity, altering reaction kinetics and translating into a dysfunctional channel phenotype with impaired metabolic signal decoding and processing capabilities. These data implicate a link between mutations in the cardioprotective KATP channel and susceptibility to myopathic disease and electrical instability. Dilated cardiomyopathy with ventricular tachycardia due to ABCC9 KATP channel mutations has been designated CMD10 (Online Mendelian Inheritance in Man no. 608569) to distinguish this entity from other etiologies causing this heterogeneous condition. The ultimate phenotype in the Kir6.2 knockout, under pressure overload, is development of heart failure with cardiac chamber dilation, a phenotype similar to that observed in patients with mutations in KATP channel genes (34, 73). Even in the absence of genetic deficit in KATP channel proteins, cardiomyocytes in heart failure undergo extensive remodeling, including diminished mitochondrial respiration, suppressed CK flux, decreased energy storage, and cytoskeletal disruption, although bulk cytosolic ATP levels are preserved (4, 11, 25, 33). These changes impact metabolic signal generation, transduction, and decoding by KATP channels. KATP channels from failing hearts display an improper response to ATP and creatine kinase, a reduced recognition of metabolic distress, and do not provide for appropriate action potential shortening upon exposure to hypoxia (25). Consequently, such hearts are excessively vulnerable to calcium loading and myocyte necrosis under stress that can be largely ameliorated by pharmacological restoration of KATP channel opening with KATP channel-opening drugs, such as nicorandil and pinacidil (25). More recently, a KATP channel mutation conferring risk for adrenergic atrial fibrillation originating from vein of Marshall was identified (49). The vein of Marshall, a remnant of the left superior vena cava rich in sympathetic fibers, is a recognized source for adrenergic atrial fibrillation. Genetic investigation uncovered a missense mutation (T1547I) also in the ABCC9 gene, encoding the SUR2A regulatory subunit of cardiac KATP channels. Structural modeling of mutant KATP channels predicted, and patch-clamp electrophysiology demonstrated, compromised function with defective stress responsiveness. Targeted knockout of the KATP channel verified the pathogenic link between channel dysfunction and predisposition to adrenergic atrial fibrillation. In this first report of genetic susceptibility to adrenergic vein of Marshall atrial fibrillation, radiofrequency ablation was curative, disrupting the gene-environment substrate for arrhythmia conferred by KATP channelopathy (49). Thus cardiac KATP channels through tight integration with cellular metabolic signaling pathways respond with high fidelity to perturbations in cellular energetics. This highly responsive integrated system adapts metabolic expenditures to available resources, resulting in an effective feedback that maintains cellular well-being under a range of physiological and pathological conditions. Further understanding of mechanisms responsible for KATP channel regulation and KATP channelopathy-associated disease susceptibility provides novel insights into endogenous cardioprotection and the development of strategies for the management of cardiovascular injury and disease progression. 103 • NOVEMBER 2007 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017 KATP channel function is recognized as vital for adaptation to physiological and pathological stress. Hearts genetically deprived of KATP channels lack stress-induced cardiac action potential shortening upon adrenergic stress (76). Indeed, loss of this regulator of membrane electrical stability in the Kir6.2knockout predisposes to cytosolic calcium overload associated with development of progressive contractile dysfunction and death under acute stress (76). On autopsy, contraction bands, pathognomonic of cytosolic calcium loading, are visible throughout the myocardium of the Kir6.2-knockout, but not wild-type, in response to -adrenergic stress (76). Similarly, under chronic stress associated with physical exertion, KATP channel knockout compromises the benefit of exercise training, resulting in cardiac functional and structural deficits (32). Thus cardiac KATP channels, harnessing the ability to recognize alterations in the metabolic state of the cell and translate this information into changes in membrane excitability, provide a link necessary for the maintenance of myocardial well-being under stress-induced energy-demanding augmentation in performance. In pathological conditions, KATP channels are recognized to also serve a vital cardioprotective role. Genetic disruption of KATP channels results in poor recovery following coronary hypoperfusion and compromises the protective benefits of ischemic preconditioning (23, 47, 58, 62), while overexpression of channel subunits generates a phenotype resistant to ischemia (17). Analogous to ischemic preconditioning, pharmacological activation of the channel through use of KATP channel openers displays cardioprotective outcome in hearts subject to ischemic challenge (23, 33, 58, 62). This pharmacological preconditioning is abolished in the absence of Kir6.2containing KATP channels (23, 33, 58, 62). In fact, Kir6.2 knockout also negates protection afforded by ischemic preconditioning on myocardial energy generation, transfer, and utilization. Total ATP turnover, a global parameter of myocardial energetic dynamics, fails to increase in the ischemic-preconditioned KATP channel knockout, as opposed to wild type, correlating with the failure of preconditioned hearts lacking KATP channels to functionally recover (23). As discussed above, the maintenance of energetic stability in the myocardium requires synchronized ATP generation and utilization accomplished through energetic phosphotransfer relay systems transferring energy from sites of production to sites of utilization and promptly removing end products from sites of utilization. In this regard, in wild-type but not Kir6.2-knockout ischemic hearts, preconditioning preserves CK phosphotransfer, the major energy transfer pathway in the heart (23, 33). Disruption of KATP channel function forms the basis for reduction in energetic production and/or consumption that contributes to contractile dysfunction. These findings may provide a mechanistic basis for the potentially deleterious outcomes associated with use of KATP channel blockers, sulfonylurea medication, in the setting of myocardial infarction (33). Defects in the function of KATP channel proteins themselves, disruption of intracellular metabolic networks, and/or disturbed communication between channel proteins and the energetic network can all contribute to susceptibility toward cardiac disease and poor outcome (11, 49). In humans, mutations in the ABCC9-encoded regulatory channel subunit SUR2A have been demonstrated in a subset of patients with dilated cardiomyopathy and ventricular arrhythmia (11) (Fig. 2). The identified 1891 Invited Review 1892 KATP CHANNELS: METABOLIC SENSING AND CARDIOPROTECTION REFERENCES J Appl Physiol • VOL 103 • NOVEMBER 2007 • www.jap.org Downloaded from http://jap.physiology.org/ by 10.220.32.247 on May 12, 2017 1. 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