P2X4-Receptor-Mediated Synthesis and Release of Brain-Derived Neurotrophic Factor in Microglia Is Dependent on Calcium and p38-Mitogen-Activated Protein Kinase Activation
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Full frame distilled prediction
Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
- Candidate categories
- none
- Consensus categories
- none
- Domain
- Candidate signal: noneConsensus signal: none
- Study design
- Candidate signal: Bench or experimentalConsensus signal: Bench or experimental
- Genre
- Candidate signal: EmpiricalConsensus signal: Empirical
- Teacher disagreement score
- 0.034
- Threshold uncertainty score
- 0.657
- Validation status
machine_predicted_unvalidated·codex-gemma-dda1882f352a
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
- Teacher spread
- 0.239 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
Microglia in the dorsal horn of the spinal cord are increasingly recognized as being crucial in the pathogenesis of pain hypersensitivity after injury to a peripheral nerve. It is known that P2X4 purinoceptors (P2X4Rs) cause the release of brain-derived neurotrophic factor (BDNF) from microglia, which is necessary for maintaining pain hypersensitivity after nerve injury. However, there is a critical gap in understanding how activation of microglial P2X4Rs leads to the release of BDNF. Here, we show that stimulating P2X4Rs with ATP evokes a biphasic release of BDNF from microglia: an early phase occurs within 5 min, whereas a late phase peaks 60 min after ATP stimulation. Concomitant with the late phase of release is an increased level of BDNF within the microglia. Both phases of BDNF release and the accumulation within the microglia are dependent on extracellular Ca(2+). The late phase of BDNF release and accumulation, but not the early phase of release, are suppressed by inhibiting transcription and translation, indicating that activation of P2X4R causes an initial release of a pre-existing pool of BDNF followed by an increase in de novo synthesis of BDNF. The release of BDNF is abolished by inhibiting SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated exocytosis. Furthermore, we find that the P2X4R-evoked release and synthesis of BDNF are dependent on activation of p38-mitogen-activated protein kinase (MAPK). Together, our findings provide a unifying mechanism for pain hypersensitivity after peripheral nerve injury through P2X4R-evoked increase in Ca(2+) and activation of p38-MAPK leading to the synthesis and exocytotic release of BDNF from microglia.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
The record
- Venue
- Journal of Neuroscience
- Topic
- Nerve injury and regeneration
- Field
- Neuroscience
- Canadian institutions
- University of TorontoHospital for Sick Children
- Funders
- Canadian Institutes of Health ResearchHoward Hughes Medical Institute
- Keywords
- MicrogliaBrain-derived neurotrophic factorNeurotrophic factorsp38 mitogen-activated protein kinasesNerve growth factorProtein kinase AMAPK/ERK pathwayTropomyosin receptor kinase BCell biologyChemistryPurinergic receptorNeurotrophinEndocrinologyInternal medicineReceptorKinaseExtracellularBiologyMedicineInflammation
- Has abstract in OpenAlex
- yes