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

Gregory M. Martin, Min Woo Sung, Show Ling Shyng

Research output: Contribution to journalReview articlepeer-review

4 Scopus citations

Abstract

ATP-sensitive potassium (KATP) 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 β-cells, KATP 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.

Original languageEnglish (US)
Article number110667
JournalMolecular and Cellular Endocrinology
Volume502
DOIs
StatePublished - Feb 15 2020

Keywords

  • ABC transporter
  • Carbamazepine
  • Congenital hyperinsulinism
  • Kir channel
  • Protein assembly
  • Protein trafficking
  • Sulfonylurea receptor
  • Sulfonylureas

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Fingerprint

Dive into the research topics of 'Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures'. Together they form a unique fingerprint.

Cite this