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ATP-sensitive K(+) (K(ATP)) channels, comprised of pore-forming Kir6.2 and regulatory SUR1 subunits, play a critical role in regulating insulin secretion. Binding of ATP to Kir6.2 inhibits, whereas interaction of MgATP with SUR1 activates, K(ATP) channels. We tested the functional effects of two Kir6.2 mutations (Y330C, F333I) that cause permanent neonatal diabetes mellitus, by heterologous expression in Xenopus oocytes. Both mutations reduced ATP inhibition and increased whole-cell currents, which in pancreatic beta-cells is expected to reduce insulin secretion and precipitate diabetes. The Y330C mutation reduced ATP inhibition both directly, by impairing ATP binding (and/or transduction), and indirectly, by stabilizing the intrinsic open state of the channel. The F333I mutation altered ATP binding/transduction directly. Both mutations also altered Kir6.2/SUR1 interactions, enhancing the stimulatory effect of MgATP (which is mediated via SUR1). This effect was particularly dramatic for the Kir6.2-F333I mutation, and was abolished by SUR1 mutations that prevent MgATP binding/hydrolysis. Further analysis of F333I heterozygous channels indicated that at least three SUR1 must bind/hydrolyse MgATP to open the mutant K(ATP) channel.
Aguilar-Bryan,
Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion.
1995, Pubmed
Aguilar-Bryan,
Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion.
1995,
Pubmed Antcliff,
Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit.
2005,
Pubmed Ashcroft,
Correlating structure and function in ATP-sensitive K+ channels.
1998,
Pubmed Ashcroft,
Type 2 diabetes mellitus: not quite exciting enough?
2004,
Pubmed Ashcroft,
Electrophysiology of the pancreatic beta-cell.
1989,
Pubmed Babenko,
SUR-dependent modulation of KATP channels by an N-terminal KIR6.2 peptide. Defining intersubunit gating interactions.
2002,
Pubmed Babenko,
The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP channels.
1999,
Pubmed Baukrowitz,
PIP2 and PIP as determinants for ATP inhibition of KATP channels.
1998,
Pubmed
,
Xenbase Clement,
Association and stoichiometry of K(ATP) channel subunits.
1997,
Pubmed Cukras,
The role of NH2-terminal positive charges in the activity of inward rectifier KATP channels.
2002,
Pubmed Detimary,
Possible links between glucose-induced changes in the energy state of pancreatic B cells and insulin release. Unmasking by decreasing a stable pool of adenine nucleotides in mouse islets.
1995,
Pubmed Drain,
KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit.
1998,
Pubmed
,
Xenbase Enkvetchakul,
ATP interaction with the open state of the K(ATP) channel.
2001,
Pubmed Fan,
Phosphoinositides decrease ATP sensitivity of the cardiac ATP-sensitive K(+) channel. A molecular probe for the mechanism of ATP-sensitive inhibition.
1999,
Pubmed Gloyn,
Relapsing diabetes can result from moderately activating mutations in KCNJ11.
2005,
Pubmed
,
Xenbase Gloyn,
Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.
2004,
Pubmed
,
Xenbase Gribble,
A novel method for measurement of submembrane ATP concentration.
2000,
Pubmed
,
Xenbase Gribble,
MgATP activates the beta cell KATP channel by interaction with its SUR1 subunit.
1998,
Pubmed
,
Xenbase Gribble,
Properties of cloned ATP-sensitive K+ currents expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase Gribble,
Sulphonylurea action revisited: the post-cloning era.
2003,
Pubmed Gribble,
The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide.
1997,
Pubmed
,
Xenbase 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 Li,
The I182 region of k(ir)6.2 is closely associated with ligand binding in K(ATP) channel inhibition by ATP.
2000,
Pubmed
,
Xenbase Light,
Molecular basis of protein kinase C-induced activation of ATP-sensitive potassium channels.
2000,
Pubmed Markworth,
ATP4- mediates closure of pancreatic beta-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites.
2000,
Pubmed Nichols,
Adenosine diphosphate as an intracellular regulator of insulin secretion.
1996,
Pubmed Proks,
Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.
2004,
Pubmed
,
Xenbase Proks,
A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome.
2005,
Pubmed
,
Xenbase Reimann,
Involvement of the n-terminus of Kir6.2 in coupling to the sulphonylurea receptor.
1999,
Pubmed
,
Xenbase Rosado,
Phosphoinositides are required for store-mediated calcium entry in human platelets.
2000,
Pubmed 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 Seino,
Physiological and pathophysiological roles of ATP-sensitive K+ channels.
2003,
Pubmed Shyng,
Membrane phospholipid control of nucleotide sensitivity of KATP channels.
1998,
Pubmed Shyng,
Octameric stoichiometry of the KATP channel complex.
1997,
Pubmed Song,
ATP modulation of ATP-sensitive potassium channel ATP sensitivity varies with the type of SUR subunit.
2001,
Pubmed
,
Xenbase Tanabe,
Direct photoaffinity labeling of the Kir6.2 subunit of the ATP-sensitive K+ channel by 8-azido-ATP.
1999,
Pubmed
,
Xenbase Tarasov,
Metabolic regulation of the pancreatic beta-cell ATP-sensitive K+ channel: a pas de deux.
2004,
Pubmed Trapp,
Identification of residues contributing to the ATP binding site of Kir6.2.
2003,
Pubmed
,
Xenbase 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 Zerangue,
A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane K(ATP) channels.
1999,
Pubmed
,
Xenbase Zingman,
Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance.
2001,
Pubmed
