{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:02:25Z","timestamp":1791270145132,"version":"4.1.0"},"reference-count":33,"publisher":"American Diabetes Association","issue":"9","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,9,1]]},"abstract":"<jats:p>The prediction that overactivity of the pancreatic ATP-sensitive K+ channel (KATP channel) underlies reduced insulin secretion and causes a diabetic phenotype in humans has recently been borne out by genetic studies implicating \u201cactivating\u201d mutations in the Kir6.2 subunit of KATP as causal in both permanent and transient neonatal diabetes. Here we characterize the channel properties of Kir6.2 mutations that underlie transient neonatal diabetes (I182V) or more severe forms of permanent neonatal diabetes (V59M, Q52R, and I296L). In all cases, the mutations result in a significant decrease in sensitivity to inhibitory ATP, which correlates with channel \u201coveractivity\u201d in intact cells. Mutations can be separated into those that directly affect ATP affinity (I182V) and those that stabilize the open conformation of the channel and indirectly reduce ATP sensitivity (V59M, Q52R, and I296L). With respect to the latter group, alterations in channel gating are also reflected in a functional \u201cuncoupling\u201d of sulfonylurea (SU) block: SU sensitivity of I182V is similar to that of wild-type mutants, but the SU sensitivity of all gating mutants is reduced, with the I296L mutant being resistant to block by tolbutamide (\u226410 mmol\/l). These results have important implications for the use of insulinotropic SU drugs as an alternative therapy to insulin injections.<\/jats:p>","DOI":"10.2337\/diabetes.54.9.2645","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"2645-2654","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":89,"title":["ATP and Sulfonylurea Sensitivity of Mutant ATP-Sensitive K+ Channels in Neonatal Diabetes"],"prefix":"10.2337","volume":"54","author":[{"given":"Joseph C.","family":"Koster","sequence":"first","affiliation":[{"name":"From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria S.","family":"Remedi","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Dao","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin G.","family":"Nichols","sequence":"additional","affiliation":[{"name":"From the Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031208140479700_R1","doi-asserted-by":"crossref","unstructured":"Ashcroft FM, Rorsman P: ATP-sensitive K+ channels: a link between B-cell metabolism and insulin secretion. Biochem Soc Trans\u200818:109\u2013111,1990","DOI":"10.1042\/bst0180109"},{"key":"2022031208140479700_R2","doi-asserted-by":"crossref","unstructured":"Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JP 4th, Boyd AE 3rd, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA: Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science\u2008268:423\u2013426,1995","DOI":"10.1126\/science.7716547"},{"key":"2022031208140479700_R3","doi-asserted-by":"crossref","unstructured":"Terauchi Y, Sakura H, Yasuda, Iwamoto K, Takahashi N, Ito K, Kasai H, Suzuki H, Ueda O, Kamada N, et al.: Pancreatic beta-cell-specific targeted disruption of glucokinase gene: diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem\u2008270:30253\u201330256,1995","DOI":"10.1074\/jbc.270.51.30253"},{"key":"2022031208140479700_R4","doi-asserted-by":"crossref","unstructured":"Ishihara H, Tashiro F, Ikuta K, Asano T, Katagiri H, Inukai K, Kikuchi M, Yazaki Y, Oka Y, Miyazaki J: Inhibition of pancreatic beta-cell glucokinase by antisense RNA expression in transgenic mice: mouse strain-dependent alteration of glucose tolerance. FEBS Lett\u2008371:329\u2013332,1995","DOI":"10.1016\/0014-5793(95)00932-Y"},{"key":"2022031208140479700_R5","doi-asserted-by":"crossref","unstructured":"Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG: Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell\u2008100:645\u2013654,2000","DOI":"10.1016\/S0092-8674(00)80701-1"},{"key":"2022031208140479700_R6","doi-asserted-by":"crossref","unstructured":"Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell GI, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR: Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes\u200853:2713\u20132718,2004","DOI":"10.2337\/diabetes.53.10.2713"},{"key":"2022031208140479700_R7","doi-asserted-by":"crossref","unstructured":"Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT: Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes [erratum in N Engl J Med\u2008351:1470,2004]. N Engl J Med\u2008350:1838\u20131849, 2004","DOI":"10.1056\/NEJMoa032922"},{"key":"2022031208140479700_R8","doi-asserted-by":"crossref","unstructured":"Vaxillaire M, Populaire C, Busiah K, Cave H, Gloyn AL, Hattersley AT, Czernichow P, Froguel P, Polak M: Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes\u200853:2719\u20132722,2004","DOI":"10.2337\/diabetes.53.10.2719"},{"key":"2022031208140479700_R9","doi-asserted-by":"crossref","unstructured":"Massa O, Iafusco D, D\u2019Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crino A, Lorini R, Cerutti F, Vanelli M, Barbetti F: KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat\u200825:22\u201327,2005","DOI":"10.1002\/humu.20124"},{"key":"2022031208140479700_R10","doi-asserted-by":"crossref","unstructured":"Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JPH, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT: Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet\u200814:925\u2013934,2005","DOI":"10.1093\/hmg\/ddi086"},{"key":"2022031208140479700_R11","unstructured":"Gloyn AL, Edghill EL, Pearson ER, Mackay D, Temple IK, Shield J, Noyes K, Freedenberg D, Gillispie KM, Lambert AP, Gale EA, Ellard S, Hattersley A: Multiple subtypes of diabetes are associated with activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the \u03b2-cell ATP-sensitive potassium channel [online abstract]. Available at http:\/\/scientificsessions.diabetes.org\/Abstracts\/index.cfm?fuseaction=Locator.DisplaysAbstractSearch"},{"key":"2022031208140479700_R12","doi-asserted-by":"crossref","unstructured":"Polak M, Shield J: Neonatal and very-early-onset diabetes mellitus. Semin Neonatol\u20089:59\u201365,2004","DOI":"10.1016\/S1084-2756(03)00064-2"},{"key":"2022031208140479700_R13","doi-asserted-by":"crossref","unstructured":"Ma D, Shield JP, Dean W, Leclerc I, Knauf C, Burcelin RR, Rutter GA, Kelsey G: Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TND. J Clin Invest\u2008114:339\u2013348,2004","DOI":"10.1172\/JCI200419876"},{"key":"2022031208140479700_R14","doi-asserted-by":"crossref","unstructured":"Zung A, Glaser B, Nimri R, Zadik Z: Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab\u200889:5504\u20135507,2004","DOI":"10.1210\/jc.2004-1241"},{"key":"2022031208140479700_R15","doi-asserted-by":"crossref","unstructured":"Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM: Molecular basis of Kir6.2 mutations associated with neonatal diabetes plus neurological features. Proc Natl Acad Sci U S A\u2008101:17539\u201317544,2004","DOI":"10.1073\/pnas.0404756101"},{"key":"2022031208140479700_R16","doi-asserted-by":"crossref","unstructured":"Enkvetchakul D, Nichols CG: Gating mechanism of KATP channels: function fits form. J Gen Physiol\u2008122:471\u2013480,2003","DOI":"10.1085\/jgp.200308878"},{"key":"2022031208140479700_R17","doi-asserted-by":"crossref","unstructured":"Koster JC, Sha Q, Nichols CG: Sulfonylurea and K(+)-channel opener sensitivity of K(ATP) channels: functional coupling of Kir6.2 and SUR1 subunits. J Gen Physiol\u2008114:203\u2013213,1999","DOI":"10.1085\/jgp.114.2.203"},{"key":"2022031208140479700_R18","doi-asserted-by":"crossref","unstructured":"Reimann F, Tucker SJ, Proks P, Ashcroft FM: Involvement of the N-terminus of Kir6.2 in coupling to the sulphonylurea receptor. J Physiol (Lond)\u2008518:325\u2013336,1999","DOI":"10.1111\/j.1469-7793.1999.0325p.x"},{"key":"2022031208140479700_R19","doi-asserted-by":"crossref","unstructured":"Cukras CA, Jeliazkova I, Nichols CG: The role of NH(2)-terminal positive charges in the activity of inward rectifier K(ATP) channels. J Gen Physiol\u2008120:437\u2013446,2002","DOI":"10.1085\/jgp.20028621"},{"key":"2022031208140479700_R20","doi-asserted-by":"crossref","unstructured":"Enkvetchakul D, Loussouarn G, Makhina E, Shyng SL, Nichols CG: The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding. Biophys J\u200878:2334\u20132348,2000","DOI":"10.1016\/S0006-3495(00)76779-8"},{"key":"2022031208140479700_R21","doi-asserted-by":"crossref","unstructured":"Neher E, Stevens CF: Conductance fluctuations and ionic pores in membranes. Annu Rev Biophys Bioeng\u20086:345\u2013381,1977","DOI":"10.1146\/annurev.bb.06.060177.002021"},{"key":"2022031208140479700_R22","doi-asserted-by":"crossref","unstructured":"Sigworth FJ: The variance of sodium current fluctuations at the node of Ranvier. J Physiol\u2008307:97\u2013129,1980","DOI":"10.1113\/jphysiol.1980.sp013426"},{"key":"2022031208140479700_R23","doi-asserted-by":"crossref","unstructured":"Shyng S, Ferrigni T, Nichols CG: Control of rectification and gating of cloned KATP channels by the Kir6.2 subunit. J Gen Physiol\u2008110:141\u2013153,1997","DOI":"10.1085\/jgp.110.2.141"},{"key":"2022031208140479700_R24","doi-asserted-by":"crossref","unstructured":"Trapp S, Proks P, Tucker SJ, Ashcroft FM: Molecular analysis of ATP-sensitive K channel gating and implications for channel inhibition by ATP. J Gen Physiol\u2008112:333\u2013349,1998","DOI":"10.1085\/jgp.112.3.333"},{"key":"2022031208140479700_R25","doi-asserted-by":"crossref","unstructured":"Drain P, Li L, Wang J: KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. Proc Natl Acad Sci U S A\u200895:13953\u201313958,1998","DOI":"10.1073\/pnas.95.23.13953"},{"key":"2022031208140479700_R26","doi-asserted-by":"crossref","unstructured":"Gribble FM, Tucker SJ, Ashcroft FM: The interaction of nucleotides with the tolbutamide block of cloned ATP-sensitive K+ channel currents expressed in Xenopus oocytes: a reinterpretation. J Physiol\u2008504:35\u201345,1997","DOI":"10.1111\/j.1469-7793.1997.00035.x"},{"key":"2022031208140479700_R27","doi-asserted-by":"crossref","unstructured":"Zunkler BJ, Trube G, Panten U: How do sulfonylureas approach their receptor in the B-cell plasma membrane?Naunyn Schmiedebergs Arch Pharmacol\u2008340:328\u2013332,1989","DOI":"10.1007\/BF00168518"},{"key":"2022031208140479700_R28","doi-asserted-by":"crossref","unstructured":"Li L, Wang J, Drain P: The I182 region of k(ir)6.2 is closely associated with ligand binding in K(ATP) channel inhibition by ATP. Biophys J\u200879:841\u2013852,2000","DOI":"10.1016\/S0006-3495(00)76340-5"},{"key":"2022031208140479700_R29","doi-asserted-by":"crossref","unstructured":"Miki T, Minami K, Zhang L, Morita M, Gonoi T, Shiuchi T, Minokoshi Y, Renaud JM, Seino S: ATP-sensitive potassium channels participate in glucose uptake in skeletal muscle and adipose tissue. Am J Physiol Endocrinol Metab\u2008283:E1178\u2212E1184,2002","DOI":"10.1152\/ajpendo.00313.2002"},{"key":"2022031208140479700_R30","doi-asserted-by":"crossref","unstructured":"Chutkow WA, Samuel V, Hansen PA, Pu J, Valdivia CR, Makielski JC, Burant CF: Disruption of Sur2-containing K(ATP) channels enhances insulin-stimulated glucose uptake in skeletal muscle. Proc Natl Acad Sci U S A\u200898:11760\u201311764,2001","DOI":"10.1073\/pnas.201390398"},{"key":"2022031208140479700_R31","doi-asserted-by":"crossref","unstructured":"Enkvetchakul D, Loussouarn G, Makhina E, Nichols CG: ATP interaction with the open state of the K(ATP) channel. Biophys J\u200880:719\u2013728,2001","DOI":"10.1016\/S0006-3495(01)76051-1"},{"key":"2022031208140479700_R32","doi-asserted-by":"crossref","unstructured":"Shyng SL, Cukras CA, Harwood J, Nichols CG: Structural determinants of PIP(2) regulation of inward rectifier K(ATP) channels. J Gen Physiol\u2008116:599\u2013608,2000","DOI":"10.1085\/jgp.116.5.599"},{"key":"2022031208140479700_R33","doi-asserted-by":"crossref","unstructured":"Ribalet B, John SA, Weiss JN: Molecular basis for Kir6.2 channel inhibition by adenine nucleotides. Biophys J\u200884:266\u2013276,2003","DOI":"10.1016\/S0006-3495(03)74847-4"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/54\/9\/2645\/382697\/zdb00905002645.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/54\/9\/2645\/382697\/zdb00905002645.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:27:34Z","timestamp":1667406454000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/54\/9\/2645\/12490\/ATP-and-Sulfonylurea-Sensitivity-of-Mutant-ATP"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,9,1]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2005,9,1]]}},"URL":"https:\/\/doi.org\/10.2337\/diabetes.54.9.2645","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,9,1]]}}}