ATP-Sensitive Potassium Channels

protein
Name = potassium inwardly-rectifying channel, subfamily J, member 11
caption =


width =
HGNCid = 6257
Symbol = KCNJ11
AltSymbols =
EntrezGene = 3767
OMIM = 600937
RefSeq = NM_000525
UniProt = Q14654
PDB =
ECnumber =
Chromosome = 11
Arm = p
Band = 15.1
LocusSupplementaryData =

ATP-sensitive potassium channels (symboled KCNJ11) are a type of potassium channel containing Kir6.0-type subunits and sulfonylurea receptors (SUR), along with additional components [cite journal | author = Stephan D, Winkler M, Kühner P, Russ U, Quast U | title = Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular K(ATP) channels. | journal = Diabetologia | volume = 49 | issue = 9 | pages = 2039–48 | year = 2006 | pmid = 16865362 | doi = 10.1007/s00125-006-0307-3] . They can be further identified by their position within the cell as being either sarcolemmal ("sarcK_ATP"), mitochondrial ("mitoK_ATP"), or nuclear ("nucK_ATP").

Discovery and Structure

SarcK_ATP are composed of eight protein subunits. Four of these are members of the inwardly rectifying potassium channel family Kir6.0 (either Kir6.1 or Kir6.2), while the other four are sulfonylurea receptors (SUR1, SUR2A, and SUR2B) [cite journal | author = Inagaki, N., Gonoi, T., Clement, JP., 4th, Namba, N., Inazawa, J., Gonzalez, G., et al. | title = Reconstitution of IKATP: An inwardrectifier subunit plus the sulfonylurea receptor. | journal = Science | volume = 270 | issue = 5239 | pages = 1166–1170 | year = 1995 | doi = 10.1126/science.270.5239.1166] . The Kir subunits have two transmembrane spans and form the channel’s pore. The SUR subunits have three additional transmembrane domains, and contain two nucleotide-binding domains on the cytoplasmic side [cite journal | author = Seino, S., & Miki, T. | title = Physiological and pathophysiological roles of ATP-sensitive K+ channels. | journal = Progress in Biophysics and Molecular Biology | volume = 81 | issue = 2 | pages = 133–176 | year = 2003 | doi = 10.1016/S0079-6107(02)00053-6] . These allow for nucleotide-mediated regulation of the potassium channel, and are critical in its roles as a sensor of metabolic status. These SUR subunits are also sensitive to sulfonylureas, MgATP, and some other pharmacological channel openers. While all sarcK_ATP are constructed of eight subunits in this 4:4 ratio, their precise composition varies with tissue type [cite journal | author = Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. | title = KATP channel: relation with cell metabolism and role in the cardiovascular system | journal = The International Journal of Biochemistry and Cell Biology | volume = 73 | issue = 4 | pages = 751–764 | year = 2005 | doi = 10.1016/j.biocel.2004.10.008] .

MitoK_ATP were first identified in 1991 by single-channel recordings of the inner mitochondrial membrane [cite journal | author = Inoue, I., Nagase, H., Kishi, K., & Higuti, T. | title = ATP-sensitive K+ channel in the mitochondrial inner membrane. | journal = Nature | volume = 352 | issue = 6332 | pages = 244–247| year = 1991 | doi = 10.1038/352244a0] . The molecular structure of mitoK_ATP is less clearly understood than that of sarcK_ATP. Some reports indicate that cardiac mitoK_ATP consist of Kir6.1 and Kir6.2 subunits, but neither SUR1 nor SUR2 [cite journal | author = Lacza, Z., Snipes, J. A., Miller, A. W., Szabo, C., Grover, G., & Busija, D. W. | title = Heart mitochondria contain functional ATP-dependent K+ channels. | journal = Journal of Molecular and Cellular Cardiology | volume = 35 | issue = 11 | pages = 1339–1347 | year = 2003 | doi = 10.1016/S0022-2828(03)00249-9] [cite journal | author = Mironova, G. D., Grigoriev, S. M., Skarga, Y. Y., Negoda, A. E.,& Kolomytkin, O. V. | title = ATP-dependent potassium channelfrom rat liver mitochondria: Inhibitory analysis, channel clusterization. | journal = Membrane and Cellular Biology | volume = 10 | issue = 5 | pages = 583–591 | year = 1997] . More recently, it was discovered that certain multiprotein complexes containing succinate dehydrogenase can provide activity similar to that of K_ATP channels [cite journal | author = Ardehali, H., Chen, Z., Ko, Y., Mejia-Alvarez, R., & Marban, E. | title = Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. | journal = Proceedings of the National Academy of Science USA | volume = 101 | issue = 32 | pages = 11880–11885 | year = 2004 | doi = 10.1073/pnas.0401703101] .

The presence of nucK_ATP was confirmed by the discovery that isolated patches of nuclear membrane possess properties, both kinetic and pharmacological, similar to plasma membrane K_ATP channels [cite journal | author = Quesada, I., Rovira, J. M., Martin, F., Roche, E., Nadal, A., & Soria, B. | title = Nuclear KATP channels trigger nuclear Ca(2+) transients that modulate nuclear function. | journal = Proceedings of the National Academy of Science USA | volume = 99 | issue = 14 | pages = 9544–9549 | year = 2002 | doi = 10.1073/pnas.142039299] .

ensor of Cell Metabolism

Regulation of Gene Expression

Four genes have been identified as members of the K_ATP gene family. The "sur1" and "kir6.2" genes are located in chr11p15.1 while "kir6.1" and "sur2" genes reside in chr12p12.1. The "kir6.1" and "kir6.2" genes encode the pore-forming subunits of the K_ATP channel, with the SUR subunits being encoded by the "sur1" (SUR1) gene or selective splicing of the "sur2" gene (SUR2A and SUR2B) [cite journal | author = Aguilar-Bryan, L., Clement, J. P., 4th, Gonzalez, G., Kunjilwar, K., Babenko, A., & Bryan, J. | title = Toward understanding the assembly and structure of KATP channels. | journal = Physiological Reviews | volume = 78 | issue = 1 | pages = 227–245 | year = 1998] .

Changes in the transcription of these genes, and thus the production of K_ATP channels, are directly linked to changes in the metabolic environment. High glucose levels, for example, induce a significant decrease in the "kir6.2" mRNA level – an effect that can be reverse by lower glucose concentration [cite journal | author = Moritz, W., Leech, C. A., Ferrer, J., & Habener, J. F. | title = Regulated expression of adenosine triphosphate-sensitive potassium channel subunits in pancreatic beta-cells. | journal = Endocrinology Journal | volume = 142 | issue = 1 | pages = 129–138 | year = 2001 | doi = 10.1210/en.142.1.129] . Similarly, 60 minutes of ischemia followed by 24 to 72 hours of reperfusion leads to an increase in "kir6.2" transcription in left ventricle rat myocytes [cite journal | author = Akao, M., Ohler, A., O’Rourke, B., & Marban, E. | title = Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. | journal = Circulation Research | volume = 88 | issue = 12 | pages = 1267–1275 | year = 2001 | doi = 10.1161/hh1201.092094] .

A mechanism has been proposed for the cell’s K_ATP reaction to hypoxia and ischemia [cite journal | author = Crawford, R. M., Jovanovic, S., Budas, G. R., Davies, A. M., Lad,H., Wenger, R. H., et al. | title = Chronic mild hypoxia protects heart-derived H9c2 cells against acute hypoxia/reoxygenation by regulating expression of the SUR2A subunit of the ATPsensitiveK+ channel. | journal = Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 31444–31455 | year = 2003 | doi = 10.1074/jbc.M303051200] . Low intracellular oxygen levels decrease the rate of metabolism by slowing the TCA cycle in the mitochondria. Unable to transfer electrons efficiently, the intracellular NAD+/NADH ratio decreases, activating phosphotidylinositol-3-kinase and extracellular signal-regulated kinases. This, in turn, upregulates "c-jun" transcription, creating a protein which binds to the "sur2" promoter.

One significant implication of the link between cellular oxidative stress and increased K_ATP production is that overall potassium transport function is directly proportional to the membrane concentration of these channels. In cases of diabetes, K_ATP channels cannot function properly, and a marked sensitivity to mild cardiac ischemia and hypoxia results from the cells' inability to adapt to adverse oxidative conditions [cite journal | author = Ren, Y., Xu, X., & Wang, X. | title = Altered mRNA expression of ATP-sensitive and inward rectifier potassium channel subunits in streptozotocin-induced diabetic rat heart and aorta. | journal = Journal of Pharmacological Science | volume = 93 | issue = 4 | pages = 478–483 | year = 2003 | doi = 10.1254/jphs.93.478] .

Metabolite Regulation

The degree to which particular compounds are able to regulate K_ATP channel opening varies with tissue type, and more specifically, with a tissue’s primary metabolic substrate.

In pancreatic beta cells, which are sustained primarily by ATP, the ADP/ATP ratio determines K_ATP activity. Under normal conditions, when ATP is relatively plentiful (10-20 nM), the channels are closed [cite journal | author = Babenko, A. P., Gonzalez, G., Aguilar-Bryan, L., & Bryan, J. | title = Reconstituted human cardiac KATP channels: Functional identitywith the native channels from the sarcolemma of human ventricular cells. | journal = Circulation Research | volume = 83 | issue = 11 | pages = 1132–1143 | year = 1998] . If the beta cells are subjected to oxygen or glucose deprivation, however, ADP levels increase and the channels open. The change from one state to the other happens remarkably quickly and with great synchronization due to C-terminus multimerization-potential among proximate K_ATP channels [cite journal | author = Markworth, E., Schwanstecher, C., & Schwanstecher, M. | title = ATP4-mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites. | journal = Diabetes | volume = 49 | issue = 9 | pages = 1413–1418 | year = 2000 | doi = 10.2337/diabetes.49.9.1413] .

Cardiomyocytes, on the other hand, derive the majority of their energy from long-chain fatty acids and their acyl-CoA equivalents. Cardiac ischemia, as it slows the oxidation of fatty acids, causes an accumulation of acyl-CoA and induces K_ATP channel opening while free fatty acids stabilize its closed conformation. This variation was demonstrated by examining transgenic mice, bred to have ATP-insensitive potassium channels. In the pancreas, these channels were always open, but remained closed in the cardiac cells [cite journal | author = Koster, J. C., Marshall, B. A., Ensor, N., Corbett, J. A., & Nichols, C. G. | title = Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. | journal = Cell | volume = 100 | issue = 6 | pages = 645–654 | year = 2000 | doi = 10.1016/S0092-8674(00)80701-1] [cite journal | author = Koster, J. C., Knopp, A., Flagg, T. P., Markova, K. P., Sha, Q., Enkvetchakul, D., et al. | title = Tolerance for ATP-insensitive K(ATP) channels in transgenic mice. | journal = Circulation Research | volume = 89 | issue = 11 | pages = 1022–1029 | year = 2001 | doi = 10.1161/hh2301.100342] .

Mitochondrial K_ATP and the Regulation of Aerobic Metabolism

Upon the onset of a cellular energy crisis, mitochondrial function tends to decline. This is due to alternating inner membrane potential, imbalanced trans-membrane ion transport, and an overproduction of free radicals, among other factors [cite journal | author = Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. | title = KATP channel: relation with cell metabolism and role in the cardiovascular system | journal = The International Journal of Biochemistry and Cell Biology | volume = 73 | issue = 4 | pages = 751–764 | year = 2005 | doi = 10.1016/j.biocel.2004.10.008] . In such a situation, mitoK_ATP channels open and close to regulate both internal Ca²⁺ concentration and the degree of membrane swelling. This helps restore proper membrane potential, allowing further H⁺ outflow, which continues to provide the proton gradient necessary for mitochondrial ATP synthesis. Without aid from the potassium channels, the depletion of high energy phosphate would outpace the rate at which ATP could be created against an unfavorable electrochemical gradient [cite journal | author = Xu, M., Wang, Y., Ayub, A., & Ashraf, M. | title = Mitochondrial K(ATP) channel activation reduces anoxic injury by restoring mitochondrial membrane potential | journal = American Journal of Physiology and Heart Circulation and Physiology | volume = 281 | issue = 3 | pages = H1295–H1303 | year = 2001] .

Nuclear and sarcolemmal K_ATP channels also contribute to the endurance of and recovery from metabolic stress. In order to conserve energy, sarcK_ATP open, reducing the duration of the action potential while nucK_ATP-mediated Ca²⁺ concentration changes within the nucleus favor the expression of protective protein genes [cite journal | author = Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. | title = KATP channel: relation with cell metabolism and role in the cardiovascular system | journal = The International Journal of Biochemistry and Cell Biology | volume = 73 | issue = 4 | pages = 751–764 | year = 2005 | doi = 10.1016/j.biocel.2004.10.008] .

Cardiovascular K_ATP Channels and Protecition from Ischemic Injury

Cardiac ischemia, while not always immediately lethal, often leads to delayed cardiomyocyte death by apoptosis, causing permanent injury to the heart muscle. One method, first described by Keith Reimer in 1986, involves subjecting the affected tissue to brief, non-lethal periods of ischemia (3-5 minutes) before the major ischemic insult. This procedure is known as ischemic preconditioning ("IPC"), and derives its effectiveness, at least in part, from K_ATP channel stimulation.

Both sarcK_ATP and mitoK_ATP are required for IPC to have its maximal effects. Selective mito K_ATP blockade with 5-hydroxydecanoic acid (“5-HD”) or MCC-134 [cite journal | author = Mubagwa, K., & Flameng, W. | title = Adenosine, adenosine receptors and myocardial protection: An updated overview. | journal = Cardiovascular Research | volume = 52 | issue = 1 | pages = 25–39 | year = 2001 | doi = 10.1016/S0008-6363(01)00358-3] completely inhibits the cardioprotection afforded by IPC, and genetic knockout of sarcK_ATP genes [cite journal | author = Suzuki, M., Saito, T., Sato, T., Tamagawa, M., Miki, T., Seino, S., et al. | title = Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice. | journal = Circulation | volume = 107 | issue = 5 | pages = 682–685 | year = 2003 | doi = 10.1161/01.CIR.0000055187.67365.81] in mice has been shown to increase the basal level of injury compared to wild type mice. This baseline protection is believed to be a result of sarcK_ATP’s ability to prevent cellular Ca²⁺ overloading and depression of force development during muscle contraction, thereby conserving scarce energy resources [cite journal | author = Gong, B., Miki, T., Seino, S., & Renaud, J. M. | title = A K(ATP) channel deficiency affects resting tension, not contractile force, during fatigue in skeletal muscle. | journal = American Journal of Physiologyand Cell Physiology | volume = 279 | issue = 5 | pages = C1351–C1358 | year = 2000] .

Absence of sarcK_ATP, in addition to attenuating the benefits of IPC, significantly impairs the myocyte’s ability to properly distribute Ca²⁺, decreasing sensitivity to sympathetic nerve signals, and predisposing the subject to arrhythmia and sudden death [cite journal | author = Zingman, L. V., Hodgson, D. M., Bast, P. H., Kane, G. C., Perez-Terzic, C., Gumina, R. J., et al. | title = Kir6.2 is required for adaptation to stress. | journal = Proceedings of the National Academy of Science USA | volume = 99 | issue = 20 | pages = 13278–13283 | year = 2002 | doi = 10.1073/pnas.212315199] . Similarly, sarcK_ATP regulates vascular smooth muscle tone, and deletion of the "kir6.2" or "sur2" genes leads to coronary artery vasospasm and death [cite journal | author = Chutkow, W. A., Pu, J., Wheeler, M. T., Wada, T., Makielski, J. C., Burant, C. F., et al. | title = Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. | journal = Journal of Clinical Investigation | volume = 110 | issue = 2 | pages = 203–208 | year = 2002] .

Upon further exploration of sarcK_ATP’s role in cardiac rhythm regulation, it was discovered that mutant forms of the channel, particularly mutations in the SUR2 subunit, were responsible for dilated cardiomyopathy, especially after ischemia/reperfusion [cite journal | author = Bienengraeber, M., Olson, T. M., Selivanov, V. A., Kathmann, E. C.,O’Cochlain, F., Gao, F., et al. | title = ABCC9 mutations identifiedin human dilated cardiomyopathy disrupt catalytic KATPchannel gating. | journal = Nature Genetics | volume = 36 | issue = 4 | pages = 382–387 | year = 2004 | doi = 10.1038/ng1329] . It is still unclear as to whether opening of K_ATP channels has completely pro- or antiarrhythmic effects. Increased potassium conductance should stabilize membrane potential during ischemic insults, reducing the extent infarct and ectopic pacemaker activity. On the other hand, potassium channel opening accelerates repolarization of the action potential, possibly inducing arrhythmic reentry [cite journal | author = Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. | title = KATP channel: relation with cell metabolism and role in the cardiovascular system | journal = The International Journal of Biochemistry and Cell Biology | volume = 73 | issue = 4 | pages = 751–764 | year = 2005 | doi = 10.1016/j.biocel.2004.10.008] .

ee also

* Cardiac_action_potential#Major_channels

References

External links

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