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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 and McClenaghan, Neville (2015) Evaluation of the role of N-methyl-d-aspartate (NMDA) receptors in insulin secreting beta-cells. European Journal of Pharmacology, 771 . pp. 107-113. [Journal article]

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DOI: 10.1016/j.ejphar.2015.12.015

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.

Item Type:Journal article
Keywords:N-methyl-d-aspartate receptor (NMDA receptor); MK-801 maleate; Homocysteine; Insulin secretion
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:32897
Deposited By: Dr Nigel Irwin
Deposited On:28 Jan 2016 12:10
Last Modified:28 Jan 2016 12:10

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