A novel SUR1‐TMD0 interaction region contributes to glucose‐dependent inhibition of pancreatic K ATP channels by bupropion

Background and Purpose Pancreatic β‐cell ATP‐sensitive potassium (K ATP ) channels play a central role in glucose homeostasis by coupling cellular metabolism to insulin secretion. Although conventional K ATP channel inhibitors are effective insulin secretagogues, their clinical use is limited by adverse effects such as hypoglycaemia. The antidepressant bupropion has been suggested to modulate K ATP channel activity; however, the underlying molecular mechanisms remain unclear. We investigated its effects on pancreatic β‐cell K ATP channels and molecular determinants underlying bupropion sensitivity. Experimental Approach Insulin secretion was assessed in pancreatic islets from wild‐type and β‐cell‐specific Kir6.2 knockout mice under basal and stimulatory glucose conditions. Electrophysiological recordings were performed in MIN6‐K8 and HEK293T cells expressing recombinant Kir6.2/SUR1 channels. AlphaFold3‐based structural modelling was employed to predict candidate interaction regions, followed by functional analysis using SUR1 W51A. Key Results Bupropion selectively enhanced insulin secretion at stimulatory glucose concentrations in wild‐type islets, but not at low glucose. This effect was abolished in β‐cell‐specific Kir6.2 knockout islets. Bupropion inhibited native K ATP currents in MIN6‐K8 cells (IC 50 = 14.4 μM). Structural modelling suggested a potential SUR1 interaction region involving W51. The W51A mutation significantly attenuated bupropion‐induced inhibition without a detectable change in basal ATP‐free single‐channel activity. Conclusion and Implications Bupropion inhibits pancreatic β‐cell K ATP channels and enhances insulin secretion in a glucose‐dependent manner. The SUR1‐TMD0 region, including residue W51, contributes to bupropion sensitivity. These findings provide mechanistic insight into the metabolic effects of bupropion and highlight the utility of AlphaFold3‐based structural modelling for identifying candidate interaction regions within K ATP channel complexes.