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.
LanguageEnglish
Pages107-113
JournalEuropean Journal of Pharmacology
Volume771
DOIs
Publication statusPublished - 10 Dec 2015

Fingerprint

Insulin-Secreting Cells
Homocysteine
Insulin
Aspartic Acid
Dizocilpine Maleate
Glucose
aspartic acid receptor
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

@article{a5c04f90c7924f06b68a50611d1895f2,
title = "Evaluation of the role of N-methyl-d-aspartate (NMDA) receptors in insulin secreting beta-cells",
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.",
keywords = "N-methyl-d-aspartate receptor (NMDA receptor), MK-801 maleate, Homocysteine, Insulin secretion",
author = "S Patterson and Nigel Irwin and H Gou-Parke and Charlotte Moffett and SM Scullion and Peter Flatt and Neville McClenaghan",
year = "2015",
month = "12",
day = "10",
doi = "10.1016/j.ejphar.2015.12.015",
language = "English",
volume = "771",
pages = "107--113",
journal = "European Journal of Pharmacology",
issn = "0014-2999",
publisher = "Elsevier",

}

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, 10.12.2015, p. 107-113.

Research output: Contribution to journalArticle

TY - JOUR

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

PY - 2015/12/10

Y1 - 2015/12/10

N2 - 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.

AB - 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.

KW - N-methyl-d-aspartate receptor (NMDA receptor)

KW - MK-801 maleate

KW - Homocysteine

KW - Insulin secretion

U2 - 10.1016/j.ejphar.2015.12.015

DO - 10.1016/j.ejphar.2015.12.015

M3 - Article

VL - 771

SP - 107

EP - 113

JO - European Journal of Pharmacology

T2 - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

ER -