Acute D-Serine Co-Agonism of β-Cell NMDA Receptors Potentiates Glucose-Stimulated Insulin Secretion and Excitatory β-Cell Membrane Activity
Open Access
- 7 January 2021
- Vol. 10 (1), 93
- https://doi.org/10.3390/cells10010093
Abstract
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.Keywords
This publication has 84 references indexed in Scilit:
- Association of Six Single Nucleotide Polymorphisms with Gestational Diabetes Mellitus in a Chinese PopulationPLOS ONE, 2011
- Pleiotropic and Age-dependent Effects of Decreased Protein Modification by O-Linked N-Acetylglucosamine on Pancreatic β-Cell Function and VascularizationPublished by Elsevier BV ,2011
- Role of angiotensin II type I receptor agonistic autoantibodies (AT1-AA) in preeclampsiaCurrent Opinion in Pharmacology, 2011
- Functional NMDA receptors with atypical properties are expressed in podocytesAmerican Journal of Physiology-Cell Physiology, 2011
- Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disordersNature Reviews Neuroscience, 2010
- Stoichiometry ofN-Methyl-d-Aspartate Receptors Within the Suprachiasmatic NucleusJournal of Neurophysiology, 2010
- Light-evoked NMDA receptor-mediated currents are reduced by blocking D-serine synthesis in the salamander retinaNeuroReport, 2010
- Glycine transport accounts for the differential role of glycine vs. d‐serine at NMDA receptor coagonist sites in the salamander retinaEuropean Journal of Neuroscience, 2010
- A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han ChinesePLoS Genetics, 2010
- D-Serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosisThe EMBO Journal, 2007