ATP-Sensitive Potassium Channels

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potassium inwardly-rectifying channel, subfamily J, member 11
Identifiers
Symbol KCNJ11
Entrez 3767
HUGO 6257
OMIM 600937
RefSeq NM_000525
UniProt Q14654
Other data
Locus Chr. 11 p15.1

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[1]. They can be further identified by their position within the cell as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").


Contents

[edit] Discovery and Structure

SarcKATP 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)[2]. 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[3]. 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 sarcKATP are constructed of eight subunits in this 4:4 ratio, their precise composition varies with tissue type[4].

MitoKATP were first identified in 1991 by single-channel recordings of the inner mitochondrial membrane[5]. The molecular structure of mitoKATP is less clearly understood than that of sarcKATP. Some reports indicate that cardiac mitoKATP consist of Kir6.1 and Kir6.2 subunits, but neither SUR1 nor SUR2[6][7]. More recently, it was discovered that certain multiprotein complexes containing succinate dehydrogenase can provide activity similar to that of KATP channels[8].

The presence of nucKATP was confirmed by the discovery that isolated patches of nuclear membrane possess properties, both kinetic and pharmacological, similar to plasma membrane KATP channels[9].


[edit] Sensor of Cell Metabolism

[edit] Regulation of Gene Expression

Four genes have been identified as members of the KATP 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 KATP channel, with the SUR subunits being encoded by the sur1 (SUR1) gene or selective splicing of the sur2 gene (SUR2A and SUR2B)[10].

Changes in the transcription of these genes, and thus the production of KATP 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[11]. 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[12].

A mechanism has been proposed for the cell’s KATP reaction to hypoxia and ischemia[13]. 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 KATP production is that overall potassium transport function is directly proportional to the membrane concentration of these channels. In cases of diabetes, KATP 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[14].


[edit] Metabolite Regulation

The degree to which particular compounds are able to regulate KATP 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 KATP activity. Under normal conditions, when ATP is relatively plentiful (10-20 nM), the channels are closed[15]. 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 KATP channels[16].

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 KATP 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[17][18].


[edit] Mitochondrial KATP 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[19]. In such a situation, mitoKATP 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[20].

Nuclear and sarcolemmal KATP channels also contribute to the endurance of and recovery from metabolic stress. In order to conserve energy, sarcKATP open, reducing the duration of the action potential while nucKATP-mediated Ca2+ concentration changes within the nucleus favor the expression of protective protein genes[21].


[edit] Cardiovascular KATP 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 KATP channel stimulation.

Both sarcKATP and mitoKATP are required for IPC to have its maximal effects. Selective mito KATP blockade with 5-hydroxydecanoic acid (“5-HD”) or MCC-134[22] completely inhibits the cardioprotection afforded by IPC, and genetic knockout of sarcKATP genes[23] 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 sarcKATP’s ability to prevent cellular Ca2+ overloading and depression of force development during muscle contraction, thereby conserving scarce energy resources[24].

Absence of sarcKATP, 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[25]. Similarly, sarcKATP regulates vascular smooth muscle tone, and deletion of the kir6.2 or sur2 genes leads to coronary artery vasospasm and death[26].

Upon further exploration of sarcKATP’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[27]. It is still unclear as to whether opening of KATP 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[28].


[edit] See also

[edit] References

  1. ^ Stephan D, Winkler M, Kühner P, Russ U, Quast U (2006). "Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular K(ATP) channels.". Diabetologia 49 (9): 2039–48. doi:10.1007/s00125-006-0307-3. PMID 16865362. 
  2. ^ Inagaki, N., Gonoi, T., Clement, JP., 4th, Namba, N., Inazawa, J., Gonzalez, G., et al. (1995). "Reconstitution of IKATP: An inward rectifier subunit plus the sulfonylurea receptor.". Science 270 (5239): 1166–1170. doi:10.1126/science.270.5239.1166. 
  3. ^ Seino, S., & Miki, T. (2003). "Physiological and pathophysiological roles of ATP-sensitive K+ channels.". Progress in Biophysics and Molecular Biology 81 (2): 133–176. doi:10.1016/S0079-6107(02)00053-6. 
  4. ^ Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. (2005). "KATP channel: relation with cell metabolism and role in the cardiovascular system". The International Journal of Biochemistry and Cell Biology 73 (4): 751–764. doi:10.1016/j.biocel.2004.10.008. 
  5. ^ Inoue, I., Nagase, H., Kishi, K., & Higuti, T. (1991). "ATP-sensitive K+ channel in the mitochondrial inner membrane.". Nature 352 (6332): 244–247. doi:10.1038/352244a0. 
  6. ^ Lacza, Z., Snipes, J. A., Miller, A. W., Szabo, C., Grover, G., & Busija, D. W. (2003). "Heart mitochondria contain functional ATP-dependent K+ channels.". Journal of Molecular and Cellular Cardiology 35 (11): 1339–1347. doi:10.1016/S0022-2828(03)00249-9. 
  7. ^ Mironova, G. D., Grigoriev, S. M., Skarga, Y. Y., Negoda, A. E., & Kolomytkin, O. V. (1997). "ATP-dependent potassium channel from rat liver mitochondria: Inhibitory analysis, channel clusterization.". Membrane and Cellular Biology 10 (5): 583–591. 
  8. ^ Ardehali, H., Chen, Z., Ko, Y., Mejia-Alvarez, R., & Marban, E. (2004). "Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity.". Proceedings of the National Academy of Science USA 101 (32): 11880–11885. doi:10.1073/pnas.0401703101. 
  9. ^ Quesada, I., Rovira, J. M., Martin, F., Roche, E., Nadal, A., & Soria, B. (2002). "Nuclear KATP channels trigger nuclear Ca(2+) transients that modulate nuclear function.". Proceedings of the National Academy of Science USA 99 (14): 9544–9549. doi:10.1073/pnas.142039299. 
  10. ^ Aguilar-Bryan, L., Clement, J. P., 4th, Gonzalez, G., Kunjilwar, K., Babenko, A., & Bryan, J. (1998). "Toward understanding the assembly and structure of KATP channels.". Physiological Reviews 78 (1): 227–245. 
  11. ^ Moritz, W., Leech, C. A., Ferrer, J., & Habener, J. F. (2001). "Regulated expression of adenosine triphosphate-sensitive potassium channel subunits in pancreatic beta-cells.". Endocrinology Journal 142 (1): 129–138. doi:10.1210/en.142.1.129. 
  12. ^ Akao, M., Ohler, A., O’Rourke, B., & Marban, E. (2001). "Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells.". Circulation Research 88 (12): 1267–1275. doi:10.1161/hh1201.092094. 
  13. ^ Crawford, R. M., Jovanovic, S., Budas, G. R., Davies, A. M., Lad, H., Wenger, R. H., et al. (2003). "Chronic mild hypoxia protects heart-derived H9c2 cells against acute hypoxia/reoxygenation by regulating expression of the SUR2A subunit of the ATPsensitive K+ channel.". Journal of Biological Chemistry 278 (33): 31444–31455. doi:10.1074/jbc.M303051200. 
  14. ^ Ren, Y., Xu, X., & Wang, X. (2003). "Altered mRNA expression of ATP-sensitive and inward rectifier potassium channel subunits in streptozotocin-induced diabetic rat heart and aorta.". Journal of Pharmacological Science 93 (4): 478–483. doi:10.1254/jphs.93.478. 
  15. ^ Babenko, A. P., Gonzalez, G., Aguilar-Bryan, L., & Bryan, J. (1998). "Reconstituted human cardiac KATP channels: Functional identity with the native channels from the sarcolemma of human ventricular cells.". Circulation Research 83 (11): 1132–1143. 
  16. ^ Markworth, E., Schwanstecher, C., & Schwanstecher, M. (2000). "ATP4-mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites.". Diabetes 49 (9): 1413–1418. doi:10.2337/diabetes.49.9.1413. 
  17. ^ Koster, J. C., Marshall, B. A., Ensor, N., Corbett, J. A., & Nichols, C. G. (2000). "Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes.". Cell 100 (6): 645–654. doi:10.1016/S0092-8674(00)80701-1. 
  18. ^ Koster, J. C., Knopp, A., Flagg, T. P., Markova, K. P., Sha, Q., Enkvetchakul, D., et al. (2001). "Tolerance for ATP-insensitive K(ATP) channels in transgenic mice.". Circulation Research 89 (11): 1022–1029. doi:10.1161/hh2301.100342. 
  19. ^ Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. (2005). "KATP channel: relation with cell metabolism and role in the cardiovascular system". The International Journal of Biochemistry and Cell Biology 73 (4): 751–764. doi:10.1016/j.biocel.2004.10.008. 
  20. ^ Xu, M., Wang, Y., Ayub, A., & Ashraf, M. (2001). "Mitochondrial K(ATP) channel activation reduces anoxic injury by restoring mitochondrial membrane potential". American Journal of Physiology and Heart Circulation and Physiology 281 (3): H1295–H1303. 
  21. ^ Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. (2005). "KATP channel: relation with cell metabolism and role in the cardiovascular system". The International Journal of Biochemistry and Cell Biology 73 (4): 751–764. doi:10.1016/j.biocel.2004.10.008. 
  22. ^ Mubagwa, K., & Flameng, W. (2001). "Adenosine, adenosine receptors and myocardial protection: An updated overview.". Cardiovascular Research 52 (1): 25–39. doi:10.1016/S0008-6363(01)00358-3. 
  23. ^ Suzuki, M., Saito, T., Sato, T., Tamagawa, M., Miki, T., Seino, S., et al. (2003). "Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice.". Circulation 107 (5): 682–685. doi:10.1161/01.CIR.0000055187.67365.81. 
  24. ^ Gong, B., Miki, T., Seino, S., & Renaud, J. M. (2000). "A K(ATP) channel deficiency affects resting tension, not contractile force, during fatigue in skeletal muscle.". American Journal of Physiology and Cell Physiology 279 (5): C1351–C1358. 
  25. ^ Zingman, L. V., Hodgson, D. M., Bast, P. H., Kane, G. C., Perez- Terzic, C., Gumina, R. J., et al. (2002). "Kir6.2 is required for adaptation to stress.". Proceedings of the National Academy of Science USA 99 (20): 13278–13283. doi:10.1073/pnas.212315199. 
  26. ^ Chutkow, W. A., Pu, J., Wheeler, M. T., Wada, T., Makielski, J. C., Burant, C. F., et al. (2002). "Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels.". Journal of Clinical Investigation 110 (2): 203–208. 
  27. ^ Bienengraeber, M., Olson, T. M., Selivanov, V. A., Kathmann, E. C., O’Cochlain, F., Gao, F., et al. (2004). "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating.". Nature Genetics 36 (4): 382–387. doi:10.1038/ng1329. 
  28. ^ Zhuo, M.-L., Huang, Y., Liu, D.-P., Liang, C.-C. (2005). "KATP channel: relation with cell metabolism and role in the cardiovascular system". The International Journal of Biochemistry and Cell Biology 73 (4): 751–764. doi:10.1016/j.biocel.2004.10.008. 

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