Abstract
Language | English |
---|---|
Pages | 107-113 |
Journal | European Journal of Pharmacology |
Volume | 771 |
DOIs | |
Publication status | Published - 10 Dec 2015 |
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Keywords
- N-methyl-d-aspartate receptor (NMDA receptor)
- MK-801 maleate
- Homocysteine
- Insulin secretion
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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, 10.12.2015, p. 107-113.Research output: Contribution to journal › Article
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 -