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

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• 作者：Steven Patterson¹ ; Nigel Irwin ; ^{n.irwin@ulster.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Hong Guo-Parke ; R. Charlotte Moffett ; Siobhan M. Scullion ; Peter R. Flatt ; Neville H. McClenaghan
• 关键词：N-methyl-D-aspartate receptor (NMDA receptor) ; MK-801 maleate ; Homocysteine ; Insulin secretion
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：771
• 期：Complete
• 页码：107-113
• 全文大小：1859 K

文摘

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.