Abstract
Activating mutations in the pore-forming Kir6.2 (KCNJ11) and regulatory sulphonylurea receptor SUR1 (ABCC8) subunits of the K-ATP channel are a common cause of transient neonatal diabetes mellitus (TNDM). We identified a new TNDM mutation (R826W) in the first nucleotide-binding domain (NBD1) of SUR1. The mutation was found in a region that heterodimerizes with NBD2 to form catalytic site 2. Functional analysis showed that this mutation decreases MgATP hydrolysis by purified maltose-binding protein MBP-NBD1 fusion proteins. Inhibition of ATP hydrolysis by MgADP or BeF was not changed. The results indicate that the ATPase cycle lingers in the post-hydrolytic MgADP. P-i-bound state, which is associated with channel activation. The extent of MgADP-dependent activation of KATP channel activity was unaffected by the R826W mutation, but the time course of deactivation was slowed. Channel inhibition by MgATP was reduced, leading to an increase in resting whole-cell currents. In pancreatic beta cells, this would lead to less insulin secretion and thereby diabetes.
Original language | English |
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Pages (from-to) | 648-654 |
Number of pages | 7 |
Journal | EMBO Reports |
Volume | 9 |
Issue number | 7 |
DOIs | |
Publication status | Published - Jul 2008 |
Keywords
- SUR1
- ABCC8
- K-ATP channel
- nucleotide-binding domain
- neonatal diabetes
- ATP hydrolysis
- SENSITIVE K+ CHANNELS
- SULFONYLUREA RECEPTOR
- KIR6.2
- SUR1
- INSULIN
- GENES
- DIMER