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ATP-sensitive K +  (K ATP ) channels composed of potassium inward-rectifier type 6.2 and sulfonylurea receptor type 1 subunits (Kir6.2/SUR1) 4  are expressed in various cells in the brain and endocrine pancreas where they couple metabolic status to membrane potential. In β-cells, increases in cytosolic [ATP/ADP] c  inhibit K ATP  channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in  ABCC8  (SUR1) or  KCNJ11  (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively. SUR1 is reported to be a Mg 2+ -dependent ATPase. A prevailing model posits that ATP hydrolysis at SUR1 is required to stimulate openings of the pore. However, recent work shows nucleotide binding, without hydrolysis, is sufficient to switch SUR1 to stimulatory conformations. The actions of nucleotides, ATP and ADP, on ND (SUR1 E1506D ) and CHI (SUR1 E1506K ) mutants, without Kir6.2, were compared to assess both models. Both substitutions significantly impair hydrolysis in SUR1 homologs. SUR1 E1506D  has greater affinity for MgATP than wildtype; SUR1 E1506K  has reduced affinity. Without Mg 2+ , SUR1 E1506K  has a greater affinity for ATP 4−  consistent with electrostatic attraction between ATP 4− , unshielded by Mg 2+ , and the basic lysine. Further analysis of ND and CHI  ABCC8  mutants in the second transmembrane and nucleotide-binding domains (TMD2 and NBD2) found a relation between their affinities for ATP (±Mg 2+ ) and their clinical phenotype. Increased affinity for ATP is associated with ND; decreased affinity with CHI. In contrast, MgADP showed a weaker relationship. Diazoxide, known to reduce insulin release in some CHI cases, potentiates switching of CHI mutants from non-stimulatory to stimulatory states consistent with diazoxide stabilizing a nucleotide-bound conformation. The results emphasize the greater importance of nucleotide binding vs. hydrolysis in the regulation of K ATP  channels  in vivo .

Neonatal Diabetes and Congenital Hyperinsulinism Caused by Mutations in ABCC8/SUR1 are Associated with Altered and Opposite Affinities for ATP and ADP