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Pharmacologic evidence for stabilization of a nucleotide‐bound, stimulatory conformation of SUR1Q1178R, an ABCC8 neonatal diabetes mutation

Mutations in ABCC8/SUR1 that generate hyperactive neuroendocrine‐type Kir6.2/SUR1 KATP channels are a cause of neonatal diabetes. Analysis of one mutant, SUR1Q1178R, is consistent with the MgATP‐dependent accumulation of a post‐hydrolytic, ADP‐bound enzymatic intermediate that stimulates channel opening. SUR1 is the target for KATP channel inhibitors, e.g., glibenclamide, and openers, e.g., diazoxide and NCC. In the Kir6.2/SUR1 channel, the mutation potentiated the negative allosteric effect of MgATP on binding of [3H]‐glibenclamide reducing the number of specific channel binding sites by ~50% whereas in wild‐type, the KD increased 4.5x. This is consistent with a greater depopulation of antagonist binding sites in the R1178 channels at steady‐state. MgATP is required for opener function and high‐affinity agonist binding. SUR1R1178 increased the apparent number of agonist binding sites, without affecting their Ki, implying these agonists interact with the stimulatory, post‐hydrolytic conformation stabilized by the R1178 substitution. The data suggest the stimulatory, post‐hydrolytic conformation could accumulate either because R1178 increases the rate of ATP hydrolysis or reduces the rate of product dissociation, and rationalize the need for a higher glibenclamide dose to reach metabolic control in ABCC8 neonatal diabetes patients.