Kir6.2 channel activity is regulated by interaction of transmembrane domains 1 and 2 through I167 in the bundle‐crossing gate

• Published in: Physiological reports Vol. 13; no. 15; pp. e70481 - n/a
• Main Authors: Kawashima, Ryoko, Meller, Charlotte, Suzuki, Manabu, Kato, Shigeki, Horita, Shoichiro, Hidema, Shizu, Misaka, Shingen, Hosoya, Mitsuaki, Go, Hayato, Kobayashi, Kazuto, de Wet, Heidi, Maejima, Yuko, Shimomura, Kenju
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2025; Wiley
• Subjects: Animals; Channel gating; Channel opening; Diabetes; Diabetes mellitus; HEK293 Cells; Humans; Insulin; Insulin secretion; Ion Channel Gating; KATP channel; Kir6.2; Ligands; Metabolism; Mutation; Neonates; Potassium; Potassium channels (inwardly-rectifying); Potassium Channels, Inwardly Rectifying - chemistry; Potassium Channels, Inwardly Rectifying - genetics; Potassium Channels, Inwardly Rectifying - metabolism; Protein Domains; Sulfonylurea; Sulfonylurea Receptors - genetics; Sulfonylurea Receptors - metabolism; SUR; Transmembrane domains; KATP channel; Kir6.2; SUR
• DOI: 10.14814/phy2.70481
• ISSN: 2051-817X

ATP‐sensitive potassium (K ATP ) channel in pancreatic β‐cells is composed of four pore‐forming inward rectifier potassium (Kir) 6.2 subunits and four regulatory sulfonylurea receptor (SUR) 1 subunits and regulate insulin secretion. Kir6.2 consists of a N‐terminal region, an outer transmembrane helix (TM1), an intramembrane region that functions as a potassium selectivity filter, an inner transmembrane helix (TM2) that forms a bundle‐crossing gate, and a C‐terminal cytoplasmic domain. Mutations in the Kir6.2 subunit can cause neonatal diabetes with severe neurological features (DEND syndrome). The DEND syndrome‐inducing I167L mutation of Kir6.2 increases the open probability ( P o ) of the K ATP channel. To investigate the gating mechanism impacted by this mutation in Kir6.2 alone, we used C‐terminus‐truncated Kir6.2 channels to ascertain the impact of I167 mutations on P o in Kir6.2 channels in the absence of SUR1. We found that I167L and I167F mutations showed an increased P o while the P o of other mutations (I167A, I167V) were unchanged when compared to wild‐type channels. By mutating residues in TM1 (W68, L72, F75) that may interact with I167, we found that a double mutation of I167L and F75A normalized the P o . These results would suggest that I167 may play an important role in stabilizing the open state of Kir6.2 channels.