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

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.
LanguageEnglish
Pages107-113
JournalEuropean Journal of Pharmacology
Volume771
Early online date10 Dec 2015
DOIs
Publication statusPublished - 15 Jan 2016

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Insulin-Secreting Cells
N-Methyl-D-Aspartate Receptors
Homocysteine
Insulin
N-Methylaspartate
Dizocilpine Maleate
Glucose
Membrane Potentials
DNA Damage
Signal Transduction
Cell Survival
Gene Expression
Membranes
Pharmaceutical Preparations
Genes

Keywords

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

Cite this

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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.",
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Evaluation of the role of N-methyl-D-aspartate (NMDA) receptors in insulin secreting beta-cells. / Patterson, S; Irwin, Nigel; Gou-Parke, H; Moffett, Charlotte; Scullion, SM; Flatt, Peter; McClenaghan, Neville.

In: European Journal of Pharmacology, Vol. 771, 15.01.2016, p. 107-113.

Research output: Contribution to journalArticle

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T1 - Evaluation of the role of N-methyl-D-aspartate (NMDA) receptors in insulin secreting beta-cells

AU - Patterson, S

AU - Irwin, Nigel

AU - Gou-Parke, H

AU - Moffett, Charlotte

AU - Scullion, SM

AU - Flatt, Peter

AU - McClenaghan, Neville

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