Abstract
Activating mutations in different domains of the ABCC8 gene-coded sulfonylurea receptor 1 (SUR1) cause neonatal diabetes. Here we show that a diabetogenic mutation in an unexplored helix preceding the ABC core of SUR1 dramatically increases open probability of (SUR1/Kir6.2)(4) channel (KATP) by reciprocally changing rates of its transitions to and from the long-lived, inhibitory ligand-stabilized closed state. This kinetic mechanism attenuates ATP and sulfonylurea inhibition, but not Mg-nucleotide stimulation, of SUR1/Kir6.2. The results suggest a key role for L0 helix in KATP gating and together with previous findings from mutant KATP clarify why many patients with neonatal diabetes require high doses of sulfonylureas.
Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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ATP-Binding Cassette Transporters / chemistry
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ATP-Binding Cassette Transporters / genetics*
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Cricetinae
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Diabetes Mellitus / genetics
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Diabetes Mellitus / metabolism*
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Humans
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Ion Channel Gating
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KATP Channels / chemistry
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KATP Channels / genetics
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KATP Channels / metabolism*
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Kinetics
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Ligands
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Models, Molecular
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Mutation*
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Potassium Channels, Inwardly Rectifying / chemistry
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Potassium Channels, Inwardly Rectifying / genetics*
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Potassium Channels, Inwardly Rectifying / metabolism
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Protein Conformation
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Receptors, Drug / chemistry
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Receptors, Drug / genetics*
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Receptors, Drug / metabolism
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Sulfonylurea Compounds / pharmacology*
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Sulfonylurea Receptors
Substances
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ABCC8 protein, human
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ATP-Binding Cassette Transporters
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KATP Channels
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Kir6.2 channel
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Ligands
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Potassium Channels, Inwardly Rectifying
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Receptors, Drug
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Sulfonylurea Compounds
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Sulfonylurea Receptors