Acute D-serine Co-agonism of β-cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-cell Membrane Activity

Cells

Alicia Wong¹  Amber Lockridge¹  Eric Gustafson¹  Emilyn U. Alejandro¹  Robert F. Miller² 

[1] Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA;Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA;

关键词: β-cell;    D-serine;    glucose homeostasis;    insulin secretion;    mice;    Grin1;   

DOI  :  10.3390/cells10010093

来源: DOAJ

【 摘 要 】

Insulin-secreting pancreatic β-cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive β-cell target, N-methyl D-aspartate receptors (NMDARs), is unclear. We used multiple models to evaluate glucose homeostasis and insulin secretion in mice with a systemic increase in D-serine (intraperitoneal injection or DAAO mutants without D-serine catabolism) or tissue-specific loss of Grin1-encoded GluN1, the D-serine binding NMDAR subunit. We also investigated the effects of D-serine ± NMDA on glucose-stimulated insulin secretion (GSIS) and β-cell depolarizing membrane oscillations, using perforated patch electrophysiology, in β-cell-containing primary isolated mouse islets. In vivo models of elevated D-serine correlated to improved blood glucose and insulin levels. In vitro, D-serine potentiated GSIS and β-cell membrane excitation, dependent on NMDAR activating conditions including GluN1 expression (co-agonist target), simultaneous NMDA (agonist), and elevated glucose (depolarization). Pancreatic GluN1-loss females were glucose intolerant and GSIS was depressed in islets from younger, but not older, βGrin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory β-cell NMDAR co-agonism but strain-dependent shifts in potency and age/sex-specific Grin1-loss phenotypes suggest that context is critical to the interpretation of data on the role of D-serine and NMDARs in β-cell function.

【 授权许可】

Unknown