The Emerging Structural Pharmacology of ATP-Sensitive Potassium Channels

Abstract

ATP-sensitive potassium channels (K ATP ) are energy sensors that participate in a range of physiological processes. These channels are also clinically validated drug targets. For decades, K ATP inhibitors are prescribed for diabetes and K ATP activators are used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our

Sulfonylurea receptor 2 (SUR2), intricate sensors for intracellular Mg‐nucleotides

“…On the other hand, KATP activators, called KATP openers, are used for the treatment of hypertension, hypoglycemia, and hair loss. [ 11 ] These therapeutic applications further emphasize the important physiological roles of KATP in human health.…”

“…[ 13 ] SUR subunits confer the surface expression of Kir6 channels, regulate the activity of Kir6, and harbor the binding site for KATP inhibitors, KATP activators, and Mg‐ADP. [ 11 ] Two genes, ABCC8 and ABCC9 , encode SUR1 and SUR2 proteins, respectively. [ 4 ] There are two different splicing isoforms of SUR2, namely, SUR2A and SUR2B, which differ in their last C‐terminal 42 amino acids (C42).…”

Functional dissection of KATP channel structures reveals the importance of a conserved interface

“…KATP channel inhibitors (insulin secretagogues) are widely used to treat diabetes. KATP activators (KATP openers) are used for the treatment of hypoglycemia, hypertension, and hair loss (Wu et al, 2022). KATP channels are hetero-octamers formed by Kir6 (Kir6.1 or Kir6.2) and SUR (SUR1, SUR2A, or SUR2B) subunits in a 4:4 ratio.…”

“…KATP channels are hetero-octamers formed by Kir6 (Kir6.1 or Kir6.2) and SUR (SUR1, SUR2A, or SUR2B) subunits in a 4:4 ratio. Four Kir6 subunits form the central channel pore, and four regulatory SUR subunits are located peripherally (Wu et al, 2022). Recent cryo-EM studies have provided high-resolution views of the pancreatic KATP channel (Kir6.2+SUR1) in multiple states (Ding et al, 2019;Lee et al, 2017;Li et al, 2017;Martin et al, 2017a;Martin et al, 2019;Martin et al, 2017b;Wang et al, 2022a;Wang et al, 2022b;Wu et al, 2018;Zhao and MacKinnon, 2021).…”