Functional and structural interactions within pancreatic ATP-sensitive potassium channels

ATP‑sensitive potassium (KATP) channels link cellular metabolism to electrical activity, a process essential for insulin secretion in pancreatic β‑cells. Dysfunction of KATP, often caused by mutations in its subunits SUR1 and Kir6.2, leads to severe neonatal insulin disorders. This dissertation characterizes two SUR1 mutations, R74W and E128K, revealing their distinct roles in SUR1–Kir6.2 coupling. R74 is required for proper folding of the SUR1 TMD0 domain, while E128K disrupts channel coupling and alters interactions with membrane PIP2. Additional studies identify a previously unrecognized SUR1–Kir6.2 interface (SUR1 E203–Kir6.2 Q52) involved in ATP regulation. These findings uncover multiple new structural and functional interactions critical for KATP channel gating.