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Pflugers Arch
2006 Dec 01;4533:323-32. doi: 10.1007/s00424-006-0112-3.
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Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes.
Girard CA
,
Shimomura K
,
Proks P
,
Absalom N
,
Castano L
,
Perez de Nanclares G
,
Ashcroft FM
.
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ATP-sensitive potassium (K(ATP)) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.2 inhibits, whereas interaction of Mg-nucleotides with SUR, activates the channel. Heterozygous activating mutations in Kir6.2 (KCNJ11) are a common cause of neonatal diabetes (ND). We assessed the functional effects of six novel Kir6.2 mutations associated with ND: H46Y, N48D, E227K, E229K, E292G, and V252A. K(ATP) channels were expressed in Xenopus oocytes and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of SUR). All mutations reduced the sensitivity of the K(ATP) channel to inhibition by MgATP, and enhanced whole-cell K(ATP) currents. Two mutations (E227K, E229K) also enhanced the intrinsic open probability of the channel, thereby indirectly reducing the channel ATP sensitivity. The other four mutations lie close to the predicted ATP-binding site and thus may affect ATP binding. In pancreatic beta cells, an increase in the K(ATP) current is expected to reduce insulin secretion and thereby cause diabetes. None of the mutations substantially affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting patients carrying these mutations may respond to these drugs.
Antcliff,
Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit.
2005, Pubmed
Antcliff,
Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit.
2005,
Pubmed
Ashcroft,
From molecule to malady.
2006,
Pubmed
Ashcroft,
Type 2 diabetes mellitus: not quite exciting enough?
2004,
Pubmed
Ashcroft,
Electrophysiology of the pancreatic beta-cell.
1989,
Pubmed
Ashcroft,
Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells.
,
Pubmed
Ashcroft,
ATP-sensitive potassium channelopathies: focus on insulin secretion.
2005,
Pubmed
Enkvetchakul,
ATP interaction with the open state of the K(ATP) channel.
2001,
Pubmed
Gloyn,
Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
2004,
Pubmed
,
Xenbase
Gloyn,
Relapsing diabetes can result from moderately activating mutations in KCNJ11.
2005,
Pubmed
,
Xenbase
Gribble,
MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit.
1998,
Pubmed
,
Xenbase
Gribble,
Sulphonylurea action revisited: the post-cloning era.
2003,
Pubmed
Gribble,
Properties of cloned ATP-sensitive K+ currents expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed
Hattersley,
Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy.
2005,
Pubmed
Inagaki,
Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.
1995,
Pubmed
John,
Molecular mechanism for ATP-dependent closure of the K+ channel Kir6.2.
2003,
Pubmed
John,
ATP sensitivity of ATP-sensitive K+ channels: role of the gamma phosphate group of ATP and the R50 residue of mouse Kir6.2.
2005,
Pubmed
Koster,
Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes.
2000,
Pubmed
Kuo,
Crystal structure of the potassium channel KirBac1.1 in the closed state.
2003,
Pubmed
Lin,
Stabilization of the activity of ATP-sensitive potassium channels by ion pairs formed between adjacent Kir6.2 subunits.
2003,
Pubmed
Massa,
KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.
2005,
Pubmed
Mikhailov,
3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1.
2005,
Pubmed
Nichols,
Adenosine diphosphate as an intracellular regulator of insulin secretion.
1996,
Pubmed
Pearson,
Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.
2006,
Pubmed
,
Xenbase
Pegan,
Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification.
2005,
Pubmed
,
Xenbase
Proks,
A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome.
2005,
Pubmed
,
Xenbase
Proks,
Functional effects of mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11), causing neonatal diabetes, and response to sulfonylurea therapy.
2006,
Pubmed
,
Xenbase
Proks,
Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP.
2005,
Pubmed
,
Xenbase
Proks,
A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes.
2006,
Pubmed
,
Xenbase
Proks,
Involvement of the N-terminus of Kir6.2 in the inhibition of the KATP channel by ATP.
1999,
Pubmed
,
Xenbase
Proks,
Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.
2004,
Pubmed
,
Xenbase
Sagen,
Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy.
2004,
Pubmed
Sakura,
Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle.
1995,
Pubmed
Shield,
Neonatal diabetes: new insights into aetiology and implications.
2000,
Pubmed
Shimomura,
Mutations at the same residue (R50) of Kir6.2 (KCNJ11) that cause neonatal diabetes produce different functional effects.
2006,
Pubmed
,
Xenbase
Shyng,
Octameric stoichiometry of the KATP channel complex.
1997,
Pubmed
Tammaro,
Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2-SUR1 interactions.
2005,
Pubmed
,
Xenbase
Temple,
Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes.
2000,
Pubmed
Trapp,
Molecular analysis of ATP-sensitive K channel gating and implications for channel inhibition by ATP.
1998,
Pubmed
,
Xenbase
Tucker,
Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor.
1997,
Pubmed
,
Xenbase
Vaxillaire,
Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients.
2004,
Pubmed
Yorifuji,
The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.
2005,
Pubmed
Zung,
Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2.
2004,
Pubmed