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 Ca(2+) and gene expression were assessed following acute (20min) and long-term (18h) 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 Ca(2+). However, combined culture of the NMDA antagonist, MK-801, with homocysteine did enhance intracellular Ca(2+) 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.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Patterson
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, United Kingdom. Electronic address: n.irwin@ulster.ac.uk.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Hong
authors.initials: H
authors.lastname: Guo-Parke
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: R Charlotte
authors.initials: RC
authors.lastname: Moffett
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Scullion
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Neville H
authors.initials: NH
authors.lastname: McClenaghan
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006710:Homocysteine / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007004:Hypoglycemic Agents; D007328:Insulin; D016194:Receptors, N-Methyl-D-Aspartate; D006710:Homocysteine; D016291:Dizocilpine Maleate; D002118:Calcium
keywords: Homocysteine; Insulin secretion; MK-801 maleate; N-methyl-D-aspartate receptor (NMDA receptor)