DEND Mutation in Kir6.2 (KCNJ11) Reveals a Flexible N-Terminal Region Critical for ATP-Sensing of the K^sub ATP^ Channel

ATP-sensitive K+-channels link metabolism and excitability in neurons, myocytes, and pancreatic islets. Mutations in the pore-forming subunit (Kir6.2; KCNJ11) cause neonatal diabetes, developmental delay, and epilepsy by decreasing sensitivity to ATP inhibition and suppressing electrical activity. M...

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Bibliographic Details
Published in:Biophysical journal 2008-11, Vol.95 (10), p.4689
Main Authors: Koster, Joseph C, Kurata, Harley T, Enkvetchakul, Decha, Nichols, Colin G
Format: Article
Language:English
Subjects:
Biophysics
Metabolism
Mutation
Neurons
Sensitivity
Online Access:Get full text
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Summary:ATP-sensitive K+-channels link metabolism and excitability in neurons, myocytes, and pancreatic islets. Mutations in the pore-forming subunit (Kir6.2; KCNJ11) cause neonatal diabetes, developmental delay, and epilepsy by decreasing sensitivity to ATP inhibition and suppressing electrical activity. Mutations of residue G53 underlie both mild (G53R,S) and severe (G53D) forms of the disease. All examined substitutions (G53D,R,S,A,C,F) reduced ATP-sensitivity, indicating an intolerance of any amino acid other than glycine. Surprisingly, each mutation reduces ATP affinity, rather than intrinsic gating, although structural modeling places G53 at a significant distance from the ATP-binding pocket. We propose that glycine is required in this location for flexibility of the distal N-terminus, and for an induced fit of ATP at the binding site. Consistent with this hypothesis, glycine substitution of the adjacent residue (Q52G) partially rescues ATP affinity of reconstituted Q52G/G53D channels. The results reveal an important feature of the noncanonical ATP-sensing mechanism of K^sub ATP^ channels. [PUBLICATION ABSTRACT]
ISSN:0006-3495
1542-0086