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

Steven Patterson, Nigel Irwin, Hong Guo-Parke, Rachel C Moffett, Siobhan Scullion, Peter Flatt, Neville McClenaghan

Research output: Contribution to journalArticle

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 Ca(2+) and gene expression were assessed following acute (20min) and long-term (18h) 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 Ca(2+). However, combined culture of the NMDA antagonist, MK-801, with homocysteine did enhance intracellular Ca(2+) 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
Number of pages7
JournalEuropean Journal of Pharmacology
Volume771
Early online date10 Dec 2015
DOIs
Publication statusPublished - Jan 2016

Keywords

  • homocysteine
  • insulin secretion
  • MK-801 maleate
  • N-methyl-D-aspartate receptor (NMDA receptor)

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