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

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 -