Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger

dc.contributor.authorBrittain, Matthew K.
dc.contributor.authorBrustovetsky, Tatiana
dc.contributor.authorSheets, Patrick L.
dc.contributor.authorBrittain, Joel M.
dc.contributor.authorKhanna, Rajesh
dc.contributor.authorCummins, Theodore R.
dc.contributor.authorBrustovetsky, Nickolay
dc.contributor.departmentPharmacology and Toxicology, School of Medicine
dc.date.accessioned2025-07-18T11:57:16Z
dc.date.available2025-07-18T11:57:16Z
dc.date.issued2012
dc.description.abstractGlutamate-induced delayed calcium dysregulation (DCD) is a causal factor leading to neuronal death. The mechanism of DCD is not clear but Ca2+ influx via N-methyl-d-aspartate receptors (NMDAR) and/or the reverse plasmalemmal Na+/Ca2+ exchanger (NCXrev) could be involved in DCD. However, the extent to which NMDAR and NCX(rev) contribute to glutamate-induced DCD is uncertain. Here, we show that both NMDAR and NCX(rev) are critical for DCD in neurons exposed to excitotoxic glutamate. In rat cultured hippocampal neurons, 25 μM glutamate produced DCD accompanied by sustained increase in cytosolic Na+ ([Na+]c) and plasma membrane depolarization. MK801 and memantine, noncompetitive NMDAR inhibitors, added shortly after glutamate, completely prevented DCD whereas AP-5, a competitive NMDAR inhibitor, failed to protect against DCD. None of the tested inhibitors lowered elevated [Na+]c or restored plasma membrane potential. In the experiments with NCX reversal by gramicidin, MK801 and memantine robustly inhibited NCXrev while AP-5 was much less efficacious. In electrophysiological patch-clamp experiments MK801 and memantine inhibited NCXrev-mediated ion currents whereas AP-5 failed. Thus, MK801 and memantine, in addition to NMDAR, inhibited NCXrev. Inhibition of NCXrev either with KB-R7943, or by collapsing Na+ gradient across the plasma membrane, or by inhibiting Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and thus preventing the increase in [Na+]c failed to preclude DCD. However, NCXrev inhibition combined with NMDAR blockade by AP-5 completely prevented DCD. Overall, our data suggest that both NMDAR and NCXrev are essential for DCD in glutamate-exposed neurons and inhibition of individual mechanism is not sufficient to prevent calcium dysregulation.
dc.eprint.versionAuthor's manuscript
dc.identifier.citationBrittain MK, Brustovetsky T, Sheets PL, et al. Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger. Neurobiol Dis. 2012;46(1):109-117. doi:10.1016/j.nbd.2011.12.051
dc.identifier.urihttps://hdl.handle.net/1805/49594
dc.language.isoen_US
dc.publisherElsevier
dc.relation.isversionof10.1016/j.nbd.2011.12.051
dc.relation.journalNeurobiology of Disease
dc.rightsPublisher Policy
dc.sourcePMC
dc.subjectCalcium dysregulation
dc.subjectNMDA receptor
dc.subjectNa+/Ca2+ exchanger
dc.subjectGlutamate
dc.subjectNeuron
dc.subjectExcitotoxicity
dc.titleDelayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger
dc.typeArticle
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Brittain2012Delayed-AAM.pdf
Size:
2.8 MB
Format:
Adobe Portable Document Format
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
2.04 KB
Format:
Item-specific license agreed upon to submission
Description: