August 29, 2024: Camden M. Driggers, Ph.D, Oregon Health and Science University

KATP channels in metabolic sensing: Mechanistic insights from CryoEM structures
KATP channels are ligand-gated potassium channels that couple cellular metabolism with membrane potential to regulate a broad range of cell activities: from hormone secretion, vasodilation, protection of cardiac and neuronal tissues against ischemic injuries, to learning and memory. Each KATP channel is composed of four inward rectifying potassium channels, Kir6.1 or Kir6.2, which form the ion-conducting pore, and four regulatory sulfonylurea receptors, SUR1, SUR2A, or SUR2B, from the ABC transporter family. Mutations in genes encoding KATP channel subunits are linked to several human diseases, including hyperinsulinism, neonatal diabetes and DEND syndrome. The importance of KATP channels in human health and disease has made them attractive drug targets. CryoEM studies have revealed how KATP channels are regulated by intracellular ATP and ADP, and membrane PIP2, and how a variant can cause neonatal diabetes. Furthermore, cryoEM structures of the KATP channel in complex with drugs illuminate mechanisms of pharmacological modulation. The mechanistic insights from these structures offer opportunities to improve KATP pharmacology for disorders caused by channel dysfunction.