Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures

摘要

ATP-sensitive potassium (K-ATP) channels are uniquely evolved protein complexes that couple cell energy levels to cell excitability. They govern a wide range of physiological processes including hormone secretion, neuronal transmission, vascular dilation, and cardiac and neuronal preconditioning against ischemic injuries. In pancreatic beta-cells, K-ATP channels composed of Kir6.2 and SUR1, encoded by KCNJ11 and ABCC8, respectively, play a key role in coupling blood glucose concentration to insulin secretion. Mutations in ABCC8 or KCNJ11 that diminish channel function result in congenital hyperinsulinism. Many of these mutations principally hamper channel biogenesis and hence trafficking to the cell surface. Several small molecules have been shown to correct channel biogenesis and trafficking defects. Here, we review studies aimed at understanding how mutations impair channel biogenesis and trafficking and how pharmacological ligands overcome channel trafficking defects, particularly highlighting recent cryo-EM structural studies which have shed light on the mechanisms of channel assembly and pharmacological chaperones.