Neonatal Diabetes Caused by Mutations in Sulfonylurea Receptor 1: Interplay between Expression and Mg-Nucleotide Gating Defects of ATP-Sensitive Potassium Channels

作者：Zhou Qing; Garin Intza; Castano Luis; Argente Jesus; Teresa Munoz Calvo Ma; Perez de Nanclares Guiomar; Shyng Show Ling^*

来源：Journal of Clinical Endocrinology & Metabolism, 2010, 95(12): E473-E478.

DOI：10.1210/jc.2010-1231

Context: ATP-sensitive potassium (K(ATP)) channels regulate insulin secretion by coupling glucose metabolism to beta-cell membrane potential. Gain-of-function mutations in the sulfonylurea receptor 1 (SUR1) or Kir6.2 channel subunit underlie neonatal diabetes.
Objective: The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect K(ATP) channel function.
Design: E208K or V324M mutant SUR1 was coexpressed with Kir6.2 in COS cells, and expression and gating properties of the resulting channels were assessed biochemically and electrophysiologically.
Results: Both E208K and V324M augment channel response to MgADP stimulation without altering sensitivity to ATP(4-) or sulfonylureas. Surprisingly, whereas E208K causes only a small increase in MgADP response consistent with the mild transient diabetes phenotype, V324M causes a severe activating gating defect. Unlike E208K, V324M also impairs channel expression at the cell surface, which is expected to dampen its functional impact on beta-cells. When either mutation was combined with a mutation in the second nucleotide binding domain of SUR1 previously shown to abolish Mg-nucleotide response, the activating effect of E208K and V324M was also abolished. Moreover, combination of E208K and V324M results in channels with Mg-nucleotide sensitivity greater than that seen in individual mutations alone.
Conclusion: The results demonstrate that E208K and V324M, located in distinct domains of SUR1, enhance transduction of Mg-nucleotide stimulation from the SUR1 nucleotide binding folds to Kir6.2. Furthermore, they suggest that diabetes severity is determined by interplay between effects of a mutation on channel expression and channel gating. (J Clin Endocrinol Metab 95: E473-E478, 2010)

• 出版日期2010-12