RO-256981

Long-term activation of NMDA receptors of pancreatic islet-cells increases oxidative stress and alters insulin secretion. Previously, we demonstrated that inhibition of GluN2B-containing NMDA receptors protects against islet-cell death. The aim of our current study was to further characterize the pathways influenced by modulating the receptors via the GluN2B subunit. To target GluN2B, the subtype-specific antagonists WMS-1410 and Ro 25-6981 were tested in mouse islet- and MIN6-cells. Our data reveal that sustained activation of NMDA receptors increases oxidative stress not only by mitochondrial dysfunction but also by stimulation of NADPH oxidases. Moreover, activation of NMDA receptors induces a K⁺ current in islet-cells. Inhibition of GluN2B but not of GluN2A prevents this. K_Ca3.1 and K_Ca1.1 channels were identified as main constituents of the NMDA-induced K⁺ current by specific inhibition with senicapoc or paxilline. Importantly, these two K_Ca channel blockers partly protect against glucolipotoxicity-mediated apoptosis. GluN2B-subunit antagonists reduce oxidative stress produced by mitochondria and NADPH oxidases, improve the mitochondrial oxygen consumption rate, downregulate the mRNA of Chop and have a protective effect on insulin secretion in islets challenged by NMDA. The latter was partially mimicked by the ER-stress chaperon and mitochondrial stabilizer tauroursodeoxycholic acid but not by solely scavenging mitoROS or unselective inhibition of NADPH oxidases. In summary, prolonged stimulation of GluN2B-containing NMDA receptors mediates β-cell dysfunction on the level of ion channel coupling and multiple stress responses. Targeting this subunit protects against most of these islet-cell damaging effects and could be an additional option for the treatment of type 2 diabetes.

N-Methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels that play a critical role in synaptic plasticity, learning, and memory in the central nervous system (CNS). These receptors assemble into functionally diverse complexes composed of GluN1, GluN2, and GluN3 subunits. Among them, GluN1/GluN2A is expressed predominantly in adult brain, and its dysfunction has been implicated in various neuropathological conditions. Recent advances have identified several GluN2A-targeted agents, including highly selective negative allosteric modulators (NAMs). Structure-activity relationship (SAR) studies of existing agents have provided valuable insights into structural modifications that enhance pharmacological properties, offering promising avenues for therapeutic development.