Compound heterozygous mutations in the SUR1 (ABCC 8) subunit of pancreatic KATPchannels cause neonatal diabetes by perturbing the coupling between Kir6.2 and SUR1 subunits
Autor: | Yu-Wen Lin, Diva D. De León, Nkecha Hughes, Alejandro Akrouh, YeouChing Hsu, Colin G. Nichols |
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Rok vydání: | 2012 |
Předmět: |
Male
Heterozygote endocrine system medicine.medical_specialty Patch-Clamp Techniques Receptors Drug Protein subunit Biophysics Gating Biology Sulfonylurea Receptors Compound heterozygosity medicine.disease_cause Biochemistry Diabetic Ketoacidosis Adenosine Triphosphate KATP Channels Internal medicine Chlorocebus aethiops medicine Animals Humans Homomeric Patch clamp Potassium Channels Inwardly Rectifying Mutation Infant Kir6.2 Cell biology Sulfonylurea Compounds Endocrinology COS Cells Sulfonylurea receptor ATP-Binding Cassette Transporters Protein Multimerization Research Paper |
Zdroj: | Channels. 6:133-138 |
ISSN: | 1933-6969 1933-6950 |
Popis: | 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 Mg(2+)) 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. (86)Rb(+) flux assays on COSm6 cells coexpressing the mutant subunits (to recapitulate the compound heterozygous state) show a 2-fold increase in basal rate of (86)Rb(+) 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 IC 50 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. |
Databáze: | OpenAIRE |
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