Ifenprodil, a NR2B-selective antagonist of NMDA receptor, inhibits reverse Na+/Ca2+ exchanger in neurons

Matthew K. Brittain, Tatiana Brustovetsky, Joel M. Brittain, Rajesh Khanna, Theodore R. Cummins, Nickolay Brustovetsky

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Glutamate-induced delayed calcium dysregulation (DCD) is causally linked to excitotoxic neuronal death. The mechanisms of DCD are not completely understood, but it has been proposed that the excessive influx of external Ca2+ is essential for DCD. The NMDA-subtype of glutamate receptor (NMDAR) and the plasmalemmal Na+/Ca2+ exchanger operating in the reverse mode (NCXrev) have been implicated in DCD. In experiments with "younger" neurons, 6-8 days in vitro (6-8 DIV), in which the NR2A-containing NMDAR expression is low, ifenprodil, an inhibitor of NR2B-containing NMDAR, completely prevented DCD whereas PEAQX, another NMDAR antagonist that preferentially interacts with NR2A-NMDAR, was without effect. With "older" neurons (13-16 DIV), in which NR2A- and NR2B-NMDARs are expressed to a greater extent, both ifenprodil and PEAQX applied separately failed to prevent DCD. However, combined application of ifenprodil and PEAQX completely averted DCD. Ifenprodil and ifenprodil-like NR2B-NMDAR antagonists Ro 25-6981 and Co 101244 but not PEAQX or AP-5 inhibited gramicidin- and Na +/NMDG-replacement-induced increases in cytosolic Ca2+ mediated predominantly by NCXrev. This suggests that ifenprodil, Ro 25-6981, and Co 101244 inhibit NCXrev. The ability of ifenprodil to inhibit NCXrev correlates with its efficacy in preventing DCD and emphasizes an important role of NCXrev in DCD. Overall our data suggest that both NR2A- and NR2B-NMDARs are involved in DCD in "older" neurons, and it is necessary to inhibit both NMDARs and NCXrev to prevent glutamate-induced DCD. Highlights: Ifenprodil alone or together with PEAQX inhibits glutamate-induced Ca dysregulation. Ifenprodil is more effective in younger (6-8 DIV) than in older (13-16 DIV) neurons. Ifenprodil but not AP-5 or PEAQX inhibits reverse Na/Ca exchanger (NCXrev). Ifenprodil-like NMDAR antagonists Ro 25-6981 and Co 101244 also inhibit NCXrev. Both NMDAR and NCXrev are essential for the glutamate-induced Ca 2+ dysregulation.

Original languageEnglish (US)
Pages (from-to)974-982
Number of pages9
JournalNeuropharmacology
Volume63
Issue number6
DOIs
StatePublished - Nov 1 2012

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Keywords

  • Calcium dysregulation
  • Glutamate
  • Na/Ca exchanger
  • Neuron
  • NMDA receptor

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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