ATP-sensitive potassium channel

Last updated
potassium inwardly-rectifying channel, subfamily J, member 8
Identifiers
Symbol KCNJ8
Alt. symbolsKir6.1
NCBI gene 3764
HGNC 6269
OMIM 600935
RefSeq NM_004982
UniProt Q15842
Other data
Locus Chr. 12 p12.1
Search for
Structures Swiss-model
Domains InterPro
potassium inwardly-rectifying channel, subfamily J, member 11
Identifiers
Symbol KCNJ11
Alt. symbolsKir6.2
NCBI gene 3767
HGNC 6257
OMIM 600937
RefSeq NM_000525
UniProt Q14654
Other data
Locus Chr. 11 p15.1
Search for
Structures Swiss-model
Domains InterPro
ATP-binding cassette, sub-family C (CFTR/MRP), member 8
Identifiers
Symbol ABCC8
Alt. symbolsSUR1
NCBI gene 6833
HGNC 59
OMIM 600509
RefSeq NM_000352
UniProt Q09428
Other data
Locus Chr. 11 p15.1
Search for
Structures Swiss-model
Domains InterPro
ATP-binding cassette, sub-family C (CFTR/MRP), member 9
Identifiers
Symbol ABCC9
Alt. symbolsSUR2A, SUR2B
NCBI gene 10060
HGNC 60
OMIM 601439
RefSeq NM_005691
UniProt O60706
Other data
Locus Chr. 12 p12.1
Search for
Structures Swiss-model
Domains InterPro

An ATP-sensitive potassium channel (or KATP channel) is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits, along with additional components. [1] KATP channels are widely distributed in plasma membranes; [2] however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").

Contents

Discovery and structure

KATP channels were first identified in cardiac myocytes by Akinori Noma in Japan. [3] Glucose-regulated KATP channel activity was found in pancreatic beta cells by Frances Ashcroft at the University of Oxford. [4] The closure of KATP channels leads to increased insulin secretion in beta cells and reduces glucagon secretion in alpha cells. [5]

SarcKATP are composed of eight protein subunits (octamer). Four of these are members of the inward-rectifier potassium ion channel family Kir6.x (either Kir6.1 or Kir6.2), while the other four are sulfonylurea receptors (SUR1, SUR2A, and SUR2B). [6] 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. [7] 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 (the magnesium salt of ATP), 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. [8]

MitoKATP were first identified in 1991 by single-channel recordings of the inner mitochondrial membrane. [9] 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. [10] [11] More recently, it was discovered that certain multiprotein complexes containing succinate dehydrogenase can provide activity similar to that of KATP channels. [12]

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. [13]

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). [14]

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 reversed by lower glucose concentration. [15] 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. [16]

A mechanism has been proposed for the cell's KATP reaction to hypoxia and ischemia. [17] 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.[ citation needed ]

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. [18]

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, ATP is the primary metabolic source, and the ATP/ADP ratio determines KATP channel activity. Under resting conditions, the weakly inwardly rectifying KATP channels in pancreatic beta cells are spontaneously active, allowing potassium ions to flow out of the cell and maintaining a negative resting membrane potential (slightly more positive than the K+ reversal potential). [19] In the presence of higher glucose metabolism, and consequently increased relative levels of ATP, the KATP channels close, causing the membrane potential of the cell to depolarize, activating voltage-gated calcium channels, and thus promoting the calcium-dependent release of insulin. [19] The change from one state to the other happens quickly and synchronously, due to C-terminus multimerization among proximate KATP channel molecules. [20]

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. [21] [22]

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. [8] 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. [23]

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. [8]

Cardiovascular KATP channels and protection from ischemic injury

Cardiac ischemia, while not always immediately lethal, often leads to delayed cardiomyocyte death by necrosis, 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.[ citation needed ]

Both sarcKATP and mitoKATP are required for IPC to have its maximal effects. Selective mitoKATP blockade with 5-hydroxydecanoic acid ("5-HD") or MCC-134 [24] completely inhibits the cardioprotection afforded by IPC, and genetic knockout of sarcKATP genes [25] 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. [26]

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. [27] Similarly, sarcKATP regulates vascular smooth muscle tone, and deletion of the kir6.2 or sur2 genes leads to coronary artery vasospasm and death. [28]

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. [29] 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. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">Uniporter</span>

Uniporters, also known as solute carriers or facilitated transporters, are a type of membrane transport protein that passively transports solutes across a cell membrane. It uses facilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration. Unlike active transport, it does not require energy in the form of ATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers. Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.

<span class="mw-page-title-main">Glibenclamide</span> Chemical compound

Glibenclamide, also known as glyburide, is an antidiabetic medication used to treat type 2 diabetes. It is recommended that it be taken together with diet and exercise. It may be used with other antidiabetic medication. It is not recommended for use by itself in type 1 diabetes. It is taken by mouth.

<span class="mw-page-title-main">ROMK</span> Potassium channel

The renal outer medullary potassium channel (ROMK) is an ATP-dependent potassium channel (Kir1.1) that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb (TAL) and potassium secretion in the cortical collecting duct (CCD) of the nephron. In humans, ROMK is encoded by the KCNJ1 gene. Multiple transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">Inward-rectifier potassium channel</span> Group of transmembrane proteins that passively transport potassium ions

Inward-rectifier potassium channels (Kir, IRK) are a specific lipid-gated subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are activated by phosphatidylinositol 4,5-bisphosphate (PIP2). The malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. The process of inward-rectification was discovered by Denis Noble in cardiac muscle cells in 1960s and by Richard Adrian and Alan Hodgkin in 1970 in skeletal muscle cells.

In molecular biology, the sulfonylurea receptors (SUR) are membrane proteins which are the molecular targets of the sulfonylurea class of antidiabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. More specifically, SUR proteins are subunits of the inward-rectifier potassium ion channels Kir6.x. The association of four Kir6.x and four SUR subunits form an ion conducting channel commonly referred to as the KATP channel.

K<sub>ir</sub>6.2 Protein-coding gene in the species Homo sapiens

Kir6.2 is a major subunit of the ATP-sensitive K+ channel, a lipid-gated inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.

<span class="mw-page-title-main">PRKCE</span> Protein-coding gene in the species Homo sapiens

Protein kinase C epsilon type (PKCε) is an enzyme that in humans is encoded by the PRKCE gene. PKCε is an isoform of the large PKC family of protein kinases that play many roles in different tissues. In cardiac muscle cells, PKCε regulates muscle contraction through its actions at sarcomeric proteins, and PKCε modulates cardiac cell metabolism through its actions at mitochondria. PKCε is clinically significant in that it is a central player in cardioprotection against ischemic injury and in the development of cardiac hypertrophy.

<span class="mw-page-title-main">ABCC8</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette transporter sub-family C member 8 is a protein that in humans is encoded by the ABCC8 gene. ABCC8 orthologs have been identified in all mammals for which complete genome data are available.

<span class="mw-page-title-main">KCNJ6</span> Protein-coding gene in the species Homo sapiens

G protein-activated inward rectifier potassium channel 2 is a protein that in humans is encoded by the KCNJ6 gene. Mutation in KCNJ6 gene has been proposed to be the cause of Keppen-Lubinsky Syndrome (KPLBS).

<span class="mw-page-title-main">KCNJ8</span> Protein-coding gene in humans

Potassium inwardly-rectifying channel, subfamily J, member 8, also known as KCNJ8, is a human gene encoding the Kir6.1 protein. A mutation in KCNJ8 has been associated with cardiac arrest in the early repolarization syndrome.

<span class="mw-page-title-main">KCNJ5</span> Protein-coding gene in the species Homo sapiens

G protein-activated inward rectifier potassium channel 4(GIRK-4) is a protein that in humans is encoded by the KCNJ5 gene and is a type of G protein-gated ion channel.

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Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2(MiRP2) is a protein that in humans is encoded by the KCNE3 gene.

<span class="mw-page-title-main">KCND3</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the KCND3 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">ENSA (gene)</span> Protein-coding gene in the species Homo sapiens

Alpha-endosulfine is a protein that in humans is encoded by the ENSA gene.

<span class="mw-page-title-main">ABCC9</span> Protein-coding gene in humans

ATP-binding cassette, sub-family C member 9 (ABCC9) also known as sulfonylurea receptor 2 (SUR2) is an ATP-binding cassette transporter that in humans is encoded by the ABCC9 gene.

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<span class="mw-page-title-main">Colin Nichols</span> English academic

Colin G. Nichols FRS is the Carl Cori Endowed Professor, and Director of the Center for Investigation of Membrane Excitability Diseases at Washington University in St. Louis, Missouri.

References

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  2. ↑ Babenko AP, Aguilar-Bryan L, Bryan J (1998). "A View of Sur/kir6.x, Katpchannels". Annual Review of Physiology. 60: 667–687. doi:10.1146/annurev.physiol.60.1.667. PMID   9558481.
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  8. 1 2 3 4 Zhuo ML, Huang Y, Liu DP, Liang CC (April 2005). "KATP channel: relation with cell metabolism and role in the cardiovascular system". Int. J. Biochem. Cell Biol. 37 (4): 751–64. doi:10.1016/j.biocel.2004.10.008. PMID   15694835.
  9. ↑ Inoue I, Nagase H, Kishi K, Higuti T (July 1991). "ATP-sensitive K+ channel in the mitochondrial inner membrane". Nature. 352 (6332): 244–7. doi:10.1038/352244a0. PMID   1857420. S2CID   4358756.
  10. ↑ Lacza Z, Snipes JA, Miller AW, Szabó C, Grover G, Busija DW (November 2003). "Heart mitochondria contain functional ATP-dependent K+ channels". J. Mol. Cell. Cardiol. 35 (11): 1339–47. doi:10.1016/S0022-2828(03)00249-9. PMID   14596790.
  11. ↑ Mironova GD, Grigoriev SM, Skarga YuYu, Negoda AE, Kolomytkin OV (1997). "ATP-dependent potassium channel from rat liver mitochondria: inhibitory analysis, channel clusterization". Membr Cell Biol. 10 (5): 583–91. PMID   9225262.
  12. ↑ Ardehali H, Chen Z, Ko Y, Mejía-Alvarez R, Marbán E (August 2004). "Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity". Proc. Natl. Acad. Sci. U.S.A. 101 (32): 11880–5. doi: 10.1073/pnas.0401703101 . PMC   511068 . PMID   15284438.
  13. ↑ Quesada I, Rovira JM, Martin F, Roche E, Nadal A, Soria B (July 2002). "Nuclear KATP channels trigger nuclear Ca(2+) transients that modulate nuclear function". Proc. Natl. Acad. Sci. U.S.A. 99 (14): 9544–9. doi: 10.1073/pnas.142039299 . PMC   123177 . PMID   12089327.
  14. ↑ Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J (January 1998). "Toward understanding the assembly and structure of KATP channels". Physiol. Rev. 78 (1): 227–45. doi:10.1152/physrev.1998.78.1.227. PMID   9457174. S2CID   11851627.
  15. ↑ Moritz W, Leech CA, Ferrer J, Habener JF (January 2001). "Regulated expression of adenosine triphosphate-sensitive potassium channel subunits in pancreatic beta-cells". Endocrinology. 142 (1): 129–38. doi: 10.1210/en.142.1.129 . PMID   11145575.
  16. ↑ Akao M, Ohler A, O'Rourke B, Marbán E (June 2001). "Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells". Circ. Res. 88 (12): 1267–75. doi: 10.1161/hh1201.092094 . PMID   11420303.
  17. ↑ Crawford RM, Jovanović S, Budas GR, Davies AM, Lad H, Wenger RH, Robertson KA, Roy DJ, Ranki HJ, Jovanović A (August 2003). "Chronic mild hypoxia protects heart-derived H9c2 cells against acute hypoxia/reoxygenation by regulating expression of the SUR2A subunit of the ATP-sensitive K+ channel". J. Biol. Chem. 278 (33): 31444–55. doi: 10.1074/jbc.M303051200 . PMC   2134977 . PMID   12791696.
  18. ↑ Ren Y, Xu X, Wang X (December 2003). "Altered mRNA expression of ATP-sensitive and inward rectifier potassium channel subunits in streptozotocin-induced diabetic rat heart and aorta". J. Pharmacol. Sci. 93 (4): 478–83. doi: 10.1254/jphs.93.478 . PMID   14737020.
  19. 1 2 Craig TJ, Ashcroft FM, Prokes P (July 2008). "How ATP Inhibits the open KATP Channel". J. Gen. Physiol. 132 (1): 131–144. doi:10.1085/jgp.200709874. PMC   2442177 . PMID   18591420.
  20. ↑ Markworth E, Schwanstecher C, Schwanstecher M (September 2000). "ATP4- mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites". Diabetes. 49 (9): 1413–8. doi:10.2337/diabetes.49.9.1413. PMID   10969823.
  21. ↑ Koster J, Marshall B, Ensor N, Corbett J, Nichols C (2000). "Targeted Overactivity of β Cell KATP Channels Induces Profound Neonatal Diabetes". Cell. 100 (6): 645–654. doi: 10.1016/S0092-8674(00)80701-1 . PMID   10761930. S2CID   16641599.
  22. ↑ Koster JC, Knopp A, Flagg TP, Markova KP, Sha Q, Enkvetchakul D, Betsuyaku T, Yamada KA, Nichols CG (2001). "Tolerance for ATP-Insensitive KATP Channels in Transgenic Mice". Circulation Research. 89 (11): 1022–9. doi: 10.1161/hh2301.100342 . PMID   11717159.
  23. ↑ Xu M, Wang Y, Ayub A, Ashraf M (September 2001). "Mitochondrial K(ATP) channel activation reduces anoxic injury by restoring mitochondrial membrane potential". Am. J. Physiol. Heart Circ. Physiol. 281 (3): H1295–303. doi:10.1152/ajpheart.2001.281.3.H1295. PMID   11514300. S2CID   19081999.
  24. ↑ Mubagwa K, Flameng W (October 2001). "Adenosine, adenosine receptors and myocardial protection: an updated overview". Cardiovasc. Res. 52 (1): 25–39. doi: 10.1016/S0008-6363(01)00358-3 . PMID   11557231. S2CID   7442045.
  25. ↑ Suzuki M, Saito T, Sato T, Tamagawa M, Miki T, Seino S, Nakaya H (February 2003). "Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice". Circulation. 107 (5): 682–5. doi:10.1161/01.CIR.0000055187.67365.81. PMID   12578868. S2CID   56186961.
  26. ↑ Gong B, Miki T, Seino S, Renaud JM (November 2000). "A K(ATP) channel deficiency affects resting tension, not contractile force, during fatigue in skeletal muscle". Am. J. Physiol., Cell Physiol. 279 (5): C1351–8. doi:10.1152/ajpcell.2000.279.5.C1351. PMID   11029282. S2CID   25717677.
  27. ↑ Zingman LV, Hodgson DM, Bast PH, Kane GC, Perez-Terzic C, Gumina RJ, Pucar D, Bienengraeber M, Dzeja PP, Miki T, Seino S, Alekseev AE, Terzic A (October 2002). "Kir6.2 is required for adaptation to stress". Proc. Natl. Acad. Sci. U.S.A. 99 (20): 13278–83. Bibcode:2002PNAS...9913278Z. doi: 10.1073/pnas.212315199 . PMC   130624 . PMID   12271142.
  28. ↑ Chutkow WA, Pu J, Wheeler MT, Wada T, Makielski JC, Burant CF, McNally EM (July 2002). "Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels". J. Clin. Invest. 110 (2): 203–8. doi:10.1172/JCI15672. PMC   151064 . PMID   12122112.
  29. ↑ Bienengraeber M, Olson TM, Selivanov VA, Kathmann EC, O'Cochlain F, Gao F, Karger AB, Ballew JD, Hodgson DM, Zingman LV, Pang YP, Alekseev AE, Terzic A (April 2004). "ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating". Nat. Genet. 36 (4): 382–7. doi:10.1038/ng1329. PMC   1995438 . PMID   15034580.

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