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'''[[Adenosine triphosphate|ATP]]-sensitive [[potassium channels]]''' (symboled [[KCNJ11]]) are a type of [[potassium channel]] containing Kir6.0-type subunits and [[sulfonylurea receptor]]s (SUR), along with additional components<ref>{{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 | id = PMID 16865362}}</ref>. They can be further identified by their position within the cell as being either [[sarcolemma|sarcolemmal]] ("sarcK<sub>ATP</sub>"), [[mitochondrial]] ("mitoK<sub>ATP</sub>"), or [[cell nucleus|nuclear]] ("nucK<sub>ATP</sub>").
'''[[Adenosine triphosphate|ATP]]-sensitive [[potassium channels]]''' (symboled [[KCNJ11]]) are a type of [[potassium channel]] containing Kir6.0-type subunits and [[sulfonylurea receptor]]s (SUR), along with additional components<ref>{{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}}</ref>. They can be further identified by their position within the cell as being either [[sarcolemma|sarcolemmal]] ("sarcK<sub>ATP</sub>"), [[mitochondrial]] ("mitoK<sub>ATP</sub>"), or [[cell nucleus|nuclear]] ("nucK<sub>ATP</sub>").




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SarcK<sub>ATP</sub> 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)<ref>{{cite journal | author = Inagaki, N., Gonoi, T., Clement, JP., 4th, Namba, N., Inazawa, J., Gonzalez, G., et al. | title = Reconstitution of IKATP: An inward
SarcK<sub>ATP</sub> 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)<ref>{{cite journal | author = Inagaki, N., Gonoi, T., Clement, JP., 4th, Namba, N., Inazawa, J., Gonzalez, G., et al. | title = Reconstitution of IKATP: An inward
rectifier subunit plus the sulfonylurea receptor. | journal = Science | volume = 270 | issue = 5239 | pages = 1166-1170 | year = 1995}}</ref>. 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<ref>{{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}}</ref>. 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<sub>ATP</sub> are constructed of eight subunits in this 4:4 ratio, their precise composition varies with tissue type<ref>{{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}}</ref>.
rectifier subunit plus the sulfonylurea receptor. | journal = Science | volume = 270 | issue = 5239 | pages = 1166–1170 | year = 1995 | doi = 10.1126/science.270.5239.1166}}</ref>. 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<ref>{{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}}</ref>. 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<sub>ATP</sub> are constructed of eight subunits in this 4:4 ratio, their precise composition varies with tissue type<ref>{{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}}</ref>.


MitoK<sub>ATP</sub> were first identified in 1991 by single-channel recordings of the inner mitochondrial membrane<ref>{{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}}</ref>. The molecular structure of mitoK<sub>ATP</sub> is less clearly understood than that of sarcK<sub>ATP</sub>. Some reports indicate that cardiac mitoK<sub>ATP</sub> consist of Kir6.1 and Kir6.2 subunits, but neither SUR1 nor SUR2<ref>{{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}}</ref><ref>{{cite journal | author = Mironova, G. D., Grigoriev, S. M., Skarga, Y. Y., Negoda, A. E.,
MitoK<sub>ATP</sub> were first identified in 1991 by single-channel recordings of the inner mitochondrial membrane<ref>{{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}}</ref>. The molecular structure of mitoK<sub>ATP</sub> is less clearly understood than that of sarcK<sub>ATP</sub>. Some reports indicate that cardiac mitoK<sub>ATP</sub> consist of Kir6.1 and Kir6.2 subunits, but neither SUR1 nor SUR2<ref>{{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}}</ref><ref>{{cite journal | author = Mironova, G. D., Grigoriev, S. M., Skarga, Y. Y., Negoda, A. E.,
& Kolomytkin, O. V. | title = ATP-dependent potassium channel
& Kolomytkin, O. V. | title = ATP-dependent potassium channel
from rat liver mitochondria: Inhibitory analysis, channel clusterization. | journal = Membrane and Cellular Biology | volume = 10 | issue = 5 | pages = 583-591 | year = 1997}}</ref>. More recently, it was discovered that certain multiprotein complexes containing succinate dehydrogenase can provide activity similar to that of K<sub>ATP</sub> channels<ref>{{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}}</ref>.
from rat liver mitochondria: Inhibitory analysis, channel clusterization. | journal = Membrane and Cellular Biology | volume = 10 | issue = 5 | pages = 583–591 | year = 1997}}</ref>. More recently, it was discovered that certain multiprotein complexes containing succinate dehydrogenase can provide activity similar to that of K<sub>ATP</sub> channels<ref>{{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}}</ref>.


The presence of nucK<sub>ATP</sub> was confirmed by the discovery that isolated patches of nuclear membrane possess properties, both kinetic and pharmacological, similar to [[plasma membrane]] K<sub>ATP</sub> channels<ref>{{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}}</ref>.
The presence of nucK<sub>ATP</sub> was confirmed by the discovery that isolated patches of nuclear membrane possess properties, both kinetic and pharmacological, similar to [[plasma membrane]] K<sub>ATP</sub> channels<ref>{{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}}</ref>.




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Four [[genes]] have been identified as members of the K<sub>ATP</sub> 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<sub>ATP</sub> channel, with the SUR subunits being encoded by the ''sur1'' (SUR1) gene or selective splicing of the ''sur2'' gene (SUR2A and SUR2B)<ref>{{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}}</ref>.
Four [[genes]] have been identified as members of the K<sub>ATP</sub> 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<sub>ATP</sub> channel, with the SUR subunits being encoded by the ''sur1'' (SUR1) gene or selective splicing of the ''sur2'' gene (SUR2A and SUR2B)<ref>{{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}}</ref>.


Changes in the [[transcription (genetics)|transcription]] of these genes, and thus the production of K<sub>ATP</sub> 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<ref>{{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}}</ref>. 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<ref>{{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}}</ref>.
Changes in the [[transcription (genetics)|transcription]] of these genes, and thus the production of K<sub>ATP</sub> 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<ref>{{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}}</ref>. 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<ref>{{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}}</ref>.


A mechanism has been proposed for the cell’s K<sub>ATP</sub> reaction to [[hypoxia]] and ischemia<ref>{{cite journal | author = Crawford, R. M., Jovanovic, S., Budas, G. R., Davies, A. M., Lad,
A mechanism has been proposed for the cell’s K<sub>ATP</sub> reaction to [[hypoxia]] and ischemia<ref>{{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 ATPsensitive
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 ATPsensitive
K+ channel. | journal = Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 31444-31455 | year = 2003}}</ref>. 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]].
K+ channel. | journal = Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 31444–31455 | year = 2003 | doi = 10.1074/jbc.M303051200}}</ref>. 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<sub>ATP</sub> production is that overall potassium transport function is directly proportional to the membrane concentration of these channels. In cases of [[diabetes]], K<sub>ATP</sub> 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<ref>{{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}}</ref>.
One significant implication of the link between cellular oxidative stress and increased K<sub>ATP</sub> production is that overall potassium transport function is directly proportional to the membrane concentration of these channels. In cases of [[diabetes]], K<sub>ATP</sub> 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<ref>{{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}}</ref>.




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In [[pancreatic]] [[beta cells]], which are sustained primarily by ATP, the [[ADP]]/ATP ratio determines K<sub>ATP</sub> activity. Under normal conditions, when ATP is relatively plentiful (10-20 nM), the channels are closed<ref>{{cite journal | author = Babenko, A. P., Gonzalez, G., Aguilar-Bryan, L., & Bryan, J. | title = Reconstituted human cardiac KATP channels: Functional identity
In [[pancreatic]] [[beta cells]], which are sustained primarily by ATP, the [[ADP]]/ATP ratio determines K<sub>ATP</sub> activity. Under normal conditions, when ATP is relatively plentiful (10-20 nM), the channels are closed<ref>{{cite journal | author = Babenko, A. P., Gonzalez, G., Aguilar-Bryan, L., & Bryan, J. | title = Reconstituted human cardiac KATP channels: Functional identity
with the native channels from the sarcolemma of human ventricular cells. | journal = Circulation Research | volume = 83 | issue = 11 | pages = 1132-1143 | year = 1998}}</ref>. 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<sub>ATP</sub> channels<ref>{{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}}</ref>.
with the native channels from the sarcolemma of human ventricular cells. | journal = Circulation Research | volume = 83 | issue = 11 | pages = 1132–1143 | year = 1998}}</ref>. 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<sub>ATP</sub> channels<ref>{{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}}</ref>.


[[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<sub>ATP</sub> 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<ref>{{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}}</ref><ref>{{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}}</ref>.
[[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<sub>ATP</sub> 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<ref>{{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}}</ref><ref>{{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}}</ref>.




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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<ref>{{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}}</ref>. In such a situation, mitoK<sub>ATP</sub> channels open and close to regulate both internal Ca<sup>2+</sup> concentration and the degree of membrane swelling. This helps restore proper membrane potential, allowing further H<sup>+</sup> 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]]<ref>{{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}}</ref>.
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<ref>{{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}}</ref>. In such a situation, mitoK<sub>ATP</sub> channels open and close to regulate both internal Ca<sup>2+</sup> concentration and the degree of membrane swelling. This helps restore proper membrane potential, allowing further H<sup>+</sup> 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]]<ref>{{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}}</ref>.


Nuclear and sarcolemmal K<sub>ATP</sub> channels also contribute to the endurance of and recovery from metabolic stress. In order to conserve energy, sarcK<sub>ATP</sub> open, reducing the duration of the [[action potential]] while nucK<sub>ATP</sub>-mediated Ca<sup>2+</sup> concentration changes within the nucleus favor the expression of protective protein genes<ref>{{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}}</ref>.
Nuclear and sarcolemmal K<sub>ATP</sub> channels also contribute to the endurance of and recovery from metabolic stress. In order to conserve energy, sarcK<sub>ATP</sub> open, reducing the duration of the [[action potential]] while nucK<sub>ATP</sub>-mediated Ca<sup>2+</sup> concentration changes within the nucleus favor the expression of protective protein genes<ref>{{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}}</ref>.




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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<sub>ATP</sub> channel stimulation.
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<sub>ATP</sub> channel stimulation.


Both sarcK<sub>ATP</sub> and mitoK<sub>ATP</sub> are required for IPC to have its maximal effects. Selective mito K<sub>ATP</sub> blockade with 5-hydroxydecanoic acid (“5-HD”) or MCC-134<ref>{{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}}</ref> completely inhibits the cardioprotection afforded by IPC, and [[genetic knockout]] of sarcK<sub>ATP</sub> genes<ref>{{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}}</ref> 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<sub>ATP</sub>’s ability to prevent cellular Ca<sup>2+</sup> overloading and depression of force development during muscle contraction, thereby conserving scarce energy resources<ref>{{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 Physiology
Both sarcK<sub>ATP</sub> and mitoK<sub>ATP</sub> are required for IPC to have its maximal effects. Selective mito K<sub>ATP</sub> blockade with 5-hydroxydecanoic acid (“5-HD”) or MCC-134<ref>{{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}}</ref> completely inhibits the cardioprotection afforded by IPC, and [[genetic knockout]] of sarcK<sub>ATP</sub> genes<ref>{{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}}</ref> 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<sub>ATP</sub>’s ability to prevent cellular Ca<sup>2+</sup> overloading and depression of force development during muscle contraction, thereby conserving scarce energy resources<ref>{{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 Physiology
and Cell Physiology | volume = 279 | issue = 5 | pages = C1351–C1358 | year = 2000}}</ref>.
and Cell Physiology | volume = 279 | issue = 5 | pages = C1351–C1358 | year = 2000}}</ref>.


Absence of sarcK<sub>ATP</sub>, in addition to attenuating the benefits of IPC, significantly impairs the myocyte’s ability to properly distribute Ca<sup>2+</sup>, decreasing sensitivity to [[sympathetic nerve]] signals, and predisposing the subject to [[arrhythmia]] and sudden death<ref>{{cite journal | author = Zingman, L. V., Hodgson, D. M., Bast, P. H., Kane, G. C., Perez-
Absence of sarcK<sub>ATP</sub>, in addition to attenuating the benefits of IPC, significantly impairs the myocyte’s ability to properly distribute Ca<sup>2+</sup>, decreasing sensitivity to [[sympathetic nerve]] signals, and predisposing the subject to [[arrhythmia]] and sudden death<ref>{{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}}</ref>. Similarly, sarcK<sub>ATP</sub> regulates vascular [[smooth muscle]] tone, and deletion of the ''kir6.2'' or ''sur2'' genes leads to [[coronary artery]] [[vasospasm]] and death<ref>{{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}}</ref>.
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}}</ref>. Similarly, sarcK<sub>ATP</sub> regulates vascular [[smooth muscle]] tone, and deletion of the ''kir6.2'' or ''sur2'' genes leads to [[coronary artery]] [[vasospasm]] and death<ref>{{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}}</ref>.


Upon further exploration of sarcK<sub>ATP</sub>’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<ref>{{cite journal | author = Bienengraeber, M., Olson, T. M., Selivanov, V. A., Kathmann, E. C.,
Upon further exploration of sarcK<sub>ATP</sub>’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<ref>{{cite journal | author = Bienengraeber, M., Olson, T. M., Selivanov, V. A., Kathmann, E. C.,
O’Cochlain, F., Gao, F., et al. | title = ABCC9 mutations identified
O’Cochlain, F., Gao, F., et al. | title = ABCC9 mutations identified
in human dilated cardiomyopathy disrupt catalytic KATP
in human dilated cardiomyopathy disrupt catalytic KATP
channel gating. | journal = Nature Genetics | volume = 36 | issue = 4 | pages = 382-387 | year = 2004}}</ref>. It is still unclear as to whether opening of K<sub>ATP</sub> 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<ref>{{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}}</ref>.
channel gating. | journal = Nature Genetics | volume = 36 | issue = 4 | pages = 382–387 | year = 2004 | doi = 10.1038/ng1329}}</ref>. It is still unclear as to whether opening of K<sub>ATP</sub> 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<ref>{{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}}</ref>.




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==External links==
==External links==
* {{cite journal | author = | title = Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. | journal = Pflugers Arch | volume = | issue = | pages = | year = | id = PMID 17021801}}
* {{cite journal | author = | title = Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. | journal = Pflugers Arch | volume = | issue = | pages = | year = | pmid = 17021801| doi = 10.1007/s00424-006-0112-3}}
* {{MeshName|KCNJ11+protein,+human}}
* {{MeshName|KCNJ11+protein,+human}}


Revision as of 15:55, 6 June 2008

potassium inwardly-rectifying channel, subfamily J, member 11
Identifiers
SymbolKCNJ11
NCBI gene3767
HGNC6257
OMIM600937
RefSeqNM_000525
UniProtQ14654
Other data
LocusChr. 11 p15.1
Search for
StructuresSwiss-model
DomainsInterPro

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").


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].


Sensor of Cell Metabolism

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].


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].


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].


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].


See also

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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help); line feed character in |title= at position 35 (help)CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: line feed character in |author= at position 65 (help); line feed character in |title= at position 32 (help)CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help); line feed character in |author= at position 66 (help); line feed character in |title= at position 157 (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: line feed character in |title= at position 63 (help)CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: line feed character in |journal= at position 31 (help)CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help); line feed character in |author= at position 65 (help)CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Explicit use of et al. in: |author= (help); line feed character in |author= at position 68 (help); line feed character in |title= at position 27 (help)CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)

External links


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