PuSH - Publikationsserver des Helmholtz Zentrums München

Matsuoka, W.* ; Suzuki, M.* ; Murao, N. ; Hidema, S.* ; Kawashima, R.* ; Wada, I.* ; Endo, S.* ; Maejima, Y.* ; Shimomura, K.*

A novel SUR1-TMD0 interaction region contributes to glucose-dependent inhibition of pancreatic KATP channels by bupropion.

Br. J. Pharmacol., DOI: 10.1111/bph.70651 (2026)
DOI PMC
BACKGROUND AND PURPOSE: Pancreatic β-cell ATP-sensitive potassium (KATP) channels play a central role in glucose homeostasis by coupling cellular metabolism to insulin secretion. Although conventional KATP 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 KATP channel activity; however, the underlying molecular mechanisms remain unclear. We investigated its effects on pancreatic β-cell KATP 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 KATP currents in MIN6-K8 cells (IC50 = 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 KATP 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 KATP channel complexes.
Altmetric
Weitere Metriken?
[➜Einloggen]
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dend Syndrome ; Katp Channel ; Sur1‐tmd0 ; Bupropion ; Insulin Secretion ; Pancreatic β‐cell; K-atp Channels; Insulin-secretion; Concise Guide; Sulfonylureas
ISSN (print) / ISBN 0007-1188
e-ISSN 1476-5381
Zeitschrift British Journal of Pharmacology
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute for Diabetes und Organoid Technology (IDOT)