Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic KATP channels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits

Yu Wen Lin, Alejandro Akrouh, Yeou Ching Hsu, Nkecha Hughes, Colin G. Nichols, Diva D. De León

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

KATP channels regulate insulin secretion by coupling β-cell metabolism to membrane excitability. These channels are comprised of a pore-forming Kir6.2 tetramer which is enveloped by four regulatory SUR1 subunits. ATP acts on Kir6.2 to stabilize the channel closed state while ADP (coordinated with Mg2+) activates channels via the SUR1 domains. Aberrations in nucleotide-binding or in coupling binding to gating can lead to hyperinsulinism or diabetes. Here, we report a case of diabetes in a 7-mo old child with compound heterozygous mutations in ABCC8 (SUR1[A30V] and SUR1[G296R]). In unison, these mutations lead to a gain of KATP channel function, which will attenuate the β-cell response to increased metabolism and will thereby decrease insulin secretion. 86Rb + flux assays on COSm6 cells coexpressing the mutant subunits (to recapitulate the compound heterozygous state) show a 2-fold increase in basal rate of 86Rb+ efflux relative to WT channels. Experiments on excised inside-out patches also reveal a slight increase in activity, manifested as an enhancement in stimulation by MgADP in channels expressing the compound heterozygous mutations or homozygous G296R mutation. In addition, the IC50 for ATP inhibition of homomeric A30V channels was increased ∼6-fold, and was increased ∼3-fold for both heteromeric A30V + WT channels or compound heterozygous (A30V + G296R) channels. Thus, each mutation makes a mechanistically distinct contribution to the channel gain-of-function that results in neonatal diabetes, and which we predict may contribute to diabetes in related carrier individuals.

Original languageEnglish
JournalChannels
Volume6
Issue number2
DOIs
StatePublished - 2012

Keywords

  • ABCC8
  • ATP
  • Compound heterozygous mutations
  • Neonatal diabetes
  • SUR1
  • Sulfonylureas

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