ArticleProceedings of the National Academy of Sciences of the United States of America2009
Coupling diverse routes of calcium entry to mitochondrial dysfunction and glutamate excitotoxicity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 115 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
115 citing papers in PubMed, 187 citations in OpenAlex.
- Trial
- Mitochondrial Calcium Uniporter protects hippocampal CA2 neurons from NMDA-induced excitotoxic injury.Molecular medicine (Cambridge, Mass.) · 2026Article
- AMPAR dysregulation in microglia drives vascular pathology in diabetic retinopathy via the P2X7R/NLRP3/IL-1β pathway.Journal of translational medicine · 2026Article
- Astrocytic PCBP1 Suppresses Ferroptosis to Restore Glutamatergic Homeostasis and Mitigate Stress-Induced Depression in Male Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Negr1 deficiency alters glutamate signalling and kynurenine pathway in a mouse model of psychiatric disorders.Scientific reports · 2026Article
- Pre-plaque glutamatergic hyperexcitability, mitochondrial dysfunction, and dendritic remodeling in the hippocampus of one-month-old 5xFAD mice.Frontiers in aging neuroscience · 2026Article
- Ceftriaxone alleviates mitochondrial damage through the inhibition of extrasynaptic NMDA receptor-mediated changes in intracellular calcium levels to improve cognitive deficits in APP/PS1 mice.Alzheimer's research & therapy · 2025Article
- How to Pick a Neuroprotective Drug in Stroke Without Losing Your Mind?Life (Basel, Switzerland) · 2025Review
- EAAT2 Activation Regulates Glutamate Excitotoxicity and Reduces Impulsivity in a Rodent Model of Parkinson's Disease.Molecular neurobiology · 2025Article
- Structure-Activity Relationship of NMDA Receptor Ligands and Their Activities on the ERK Activation through Metabotropic Signaling Pathway.Biomolecules & therapeutics · 2025Article
- Sodium Thiosulfate: An Innovative Multi-Target Repurposed Treatment Strategy for Late-Onset Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Research Progress on NMDA Receptor Enhancement Drugs for the Treatment of Depressive Disorder.CNS drugs · 2024Review
- The neuropathobiology of multiple sclerosis.Nature reviews. Neuroscience · 2024Review
- Mitochondrial Calcium Waves by Electrical Stimulation in Cultured Hippocampal Neurons.Molecular neurobiology · 2024Article
- Locally Synthetized 17-β-Estradiol Reverses Amyloid-β-42-Induced Hippocampal Long-Term Potentiation Deficits.International journal of molecular sciences · 2024Article
- GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology.Neuroscience bulletin · 2023Review
- Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer's disease.Molecular neurodegeneration · 2023Review
- Cortical Spreading Depolarization and Delayed Cerebral Ischemia; Rethinking Secondary Neurological Injury in Subarachnoid Hemorrhage.International journal of molecular sciences · 2023Review
- α7 Nicotinic acetylcholine receptor: a key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect.Journal of neuroinflammation · 2023Review
55 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Overactivation of NMDA receptors (NMDARs) is a critical early step in glutamate-evoked excitotoxic injury of CNS neurons. Distinct NMDAR-coupled pathways specified by, for example, receptor location or subunit composition seem to govern glutamate-induced excitotoxic death, but there is much uncertainty concerning the underlying mechanisms of pathway selection. Here we ask whether, and if so how, route-specific vulnerability is coupled to Ca(2+) overload and mitochondrial dysfunction, which is also a known, central component of exitotoxic injury. In cultured hippocampal neurons, overactivation of only extrasynaptic NMDARs resulted in Ca(2+) entry strong enough to promote Ca(2+) overload, which subsequently leads to mitochondrial dysfunction and cell death. Receptor composition per se appears not to be a primary factor for specifying signal coupling, as NR2B inhibition abolished Ca(2+) loading and was protective only in predominantly NR2B-expressing young neurons. In older neurons expressing comparable levels of NR2A- and NR2B-containing NMDARs, amelioration of Ca(2+) overload required the inhibition of extrasynaptic receptors containing both NR2 subunits. Prosurvival synaptic stimuli also evoked Ca(2+) entry through both N2A- and NR2B-containing NMDARs, but, in contrast to excitotoxic activation of extrasynaptic NMDARs, produced only low-amplitude cytoplasmic Ca(2+) spikes and modest, nondamaging mitochondrial Ca(2+) accumulation. The results--showing that the various routes of excitotoxic Ca(2+) entry converge on a common pathway involving Ca(2+) overload-induced mitochondrial dysfunction--reconcile and unify many aspects of the "route-specific" and "calcium load-dependent" views of exitotoxic injury.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.