Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity
| Autor: | Alicia Wong, Robert F. Miller, Eric C. Gustafson, Emilyn U. Alejandro, Amber D Lockridge |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Agonist
Blood Glucose Male medicine.medical_specialty insulin secretion mice N-Methylaspartate medicine.drug_class medicine.medical_treatment Context (language use) D-serine Nerve Tissue Proteins Models Biological Receptors N-Methyl-D-Aspartate Article Grin1 Internal medicine Insulin-Secreting Cells Glucose Intolerance medicine Serine Glucose homeostasis glucose homeostasis Animals Homeostasis Receptor lcsh:QH301-705.5 Mice Knockout Sex Characteristics Chemistry Insulin Depolarization General Medicine NMDA receptor β-cell Mice Inbred C57BL Disease Models Animal Endocrinology Glucose Phenotype lcsh:Biology (General) Excitatory postsynaptic potential Female |
| Zdroj: | Cells Volume 10 Issue 1 Cells, Vol 10, Iss 93, p 93 (2021) |
| ISSN: | 2073-4409 |
| Popis: | Insulin-secreting pancreatic &beta cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive &beta 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 &beta cell depolarizing membrane oscillations, using perforated patch electrophysiology, in &beta 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 &beta 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, &beta Grin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory &beta 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 &beta cell function. |
| Databáze: | OpenAIRE |
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