Small-Molecule Sarco/Endoplasmic Reticulum Ca²⁺-ATPase Activators Reverse Methylglyoxal-Induced Inhibition through Nonantioxidant Mechanisms.

ABSTRACT: Impaired endoplasmic reticulum (ER) Ca²⁺ homeostasis contributes to β-cell dysfunction under diabetic stressors such as methylglyoxal (MGX), a reactive byproduct that induces oxidative protein modifications and advanced glycation end-products. The calcium pump sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), essential for ER Ca²⁺ regulation, is inhibited by MGX-mediated carbonylation and thiol oxidation. Pharmacological SERCA activation has emerged as a promising strategy to restore ER Ca²⁺ balance, but whether protection results from direct allosteric modulation, indirect antioxidant effects, or both has remained unclear. Herein, it is shown that novel, potent synthetic activators directly stimulate SERCA and restore its activity following MGX-i

SUBMITTER: Cruz-Cortes C 

PROVIDER: S-EPMC12716067 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature