Evaluation of the role of N-methyl-d-aspartate (NMDA) receptors in insulin secreting beta-cells

S Patterson, Nigel Irwin, H Gou-Parke, Charlotte Moffett, SM Scullion, Peter Flatt, Neville McClenaghan

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The possibility that antagonism of N-methyl-d-aspartate (NMDA) receptors represent a novel drug target for diabetes prompted the current studies probing NMDA receptor function in the detrimental actions of homocysteine on pancreatic beta-cell function. Cellular insulin content and release, changes in membrane potential and intracellular Ca2+ and gene expression were assessed following acute (20 min) and long-term (18 h) exposure of pancreatic clonal BRIN-BD11 beta-cells to known NMDA receptor modulators in the absence and presence of cytotoxic concentrations of homocysteine. As expected, acute or long-term exposure to homocysteine significantly suppressed basal and secretagogue-induced insulin release. In addition, NMDA reduced glucose-stimulated insulin secretion (GSIS). Interestingly, the selective NMDA receptor antagonist, MK-801, had no negative effects on GSIS. The effects of the NMDA receptor modulators were largely independent of effects on membrane depolarisation and increases of intracellular Ca2+. However, combined culture of the NMDA antagonist, MK-801, with homocysteine did enhance intracellular Ca2+ levels. Actions of NMDA agonists/antagonists and homocysteine on signal transduction pathways were independent of changes in cellular insulin content, cell viability, DNA damage or expression of key beta-cell genes. Taken together, the data support a role for NMDA receptors in controlling pancreatic beta-cell function. However, modulation of NMDA receptor function was unable to prevent the detrimental beta-cell effects of homocysteine.
Original languageEnglish
Pages (from-to)107-113
JournalEuropean Journal of Pharmacology
Volume771
DOIs
Publication statusPublished - 10 Dec 2015

Keywords

  • N-methyl-d-aspartate receptor (NMDA receptor)
  • MK-801 maleate
  • Homocysteine
  • Insulin secretion

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