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Mechanism of KATP hyperactivity and sulfonylurea tolerance due to a diabetogenic mutation in L0 helix of sulfonylurea receptor 1 (ABCC8)
Author(s) -
Babenko Andrey P.,
Vaxillaire Martine
Publication year - 2011
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2011.10.020
Subject(s) - sulfonylurea receptor , sulfonylurea , helix (gastropod) , mutation , mutant , chemistry , gating , medicine , endocrinology , pharmacology , diabetes mellitus , biology , gene , biochemistry , protein subunit , biophysics , snail , ecology
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.