Influence of NMDA receptor activation and subtype-specific modulation on mouse pancreatic islets

Question The NMDA receptor (NMDAR) is being discussed as a possible target for antidiabetic drugs. Our study aims to elucidate how these ion channels affect membrane potential and calcium oscillations of pancreatic islets. In addition, we examined the potential of GluN2B subtype-specific inhibition of NMDARs to increase insulin release and to maintain cell viability.

Methods Islets or β-cells were isolated from C57Bl 6 / N mice. Electrical activity was measured with microelectrode arrays. Insulin release was determined by radioimmunoassay. [Ca2+]c was analysed by fluorescence microscopy and apoptosis by TUNEL staining.

Results Glucose-stimulated insulin secretion and the electrical activity of islets did not change when NMDA / glycine (500 / 10 µM) were added acutely. When islets were pre-incubated with NMDA / glycine for 24 h, the insulin release evoked by a 15-mM glucose stimulus was significantly decreased (3.17±0.97 vs. 2.1±0.9 ng insulin / (islet*h), n = 7, p = 0.0008). By contrast, electrical activity and mean [Ca2+]c of islets measured under the same conditions were unaffected. Single β-cells treated with NMDA / glycine for 18 h revealed a significant increase in cell death (1.4±0.3 vs. 6±2 %, n = 8, p = 0.0002). Co-incubation with WMS-1410 (1 µM), a GluN2B-subunit specific NMDAR inhibitor, reduced the rate of apoptosis to 3±1 % (n = 8, p = 0.0004 vs. NMDA / glycine). Additionally, WMS-1410 also reversed the detrimental effect of NMDA / glycine on insulin secretion.

Conclusion Sustained activation of NMDARs elevates cell death, thereby harming insulin secretion. The pathway seems not to involve impairment of membrane potential oscillations. Targeting the GluN2B subunit is protective and may prevent β-cell death under pathophysiological circumstances like diabetes mellitus.

Publication History

Article published online:
06 May 2021