Signalling transduction events involved in agonist‐induced <scp>PGE</scp>2/<scp>EP</scp>4 receptor externalization in cultured rat dorsal root ganglion neurons
Bibliographic record
Abstract
BACKGROUND: Prostaglandin E2 (PGE2) enriched in inflamed tissues contributes to chronic pain by sensitizing nociceptive dorsal root ganglion (DRG) neurons (nociceptors). Of four PGE2 receptors (EP1-4), EP4 plays a major role in PGE2-induced nociceptor sensitization. We have previously reported that PGE2 or EP4 agonists stimulated EP4 externalization in cultured DRG neurons and this event contributes to nociceptor sensitization. However, the signalling transduction events governing this event remain unknown. METHODS: In this study, using antibody-based externalization assay, we examined EP subtypes and multiple signalling transduction events involved in PGE2-induced EP4 externalization in cultured DRG neurons. RESULTS: In addition to EP4 agonist, EP2 agonist, to a lesser extent, also induced EP4 externalization while EP1 and EP3 agonists had no effect. The extracellular and intracellular calcium chelators, the inhibitors of CaMKII, cAMP, PKA, PKC, PKCε, PLC, MAPKs, PI3K and Akt suppressed agonist-induced EP4 externalization. The activator of AC, two PKA-specific cAMP analogues and one Epac-specific cAMP analogue also induced EP4 externalization. ELISA showed that double sequential exposures to EP4 agonists induced a greater release of pain peptide CGRP from cultured DRG neurons than a single exposure, an event blocked by the inhibitor of anterograde transport from ER/Golgi complex to cell surface. CONCLUSIONS: Taken together, these data suggest that mobilization of extracellular and intracellular calcium as well as the activation of CaMKII, cAMP/PKA, cAMP/Epac, PKC/PKCε, MAPKs, PI3K-Akt and PLC signalling transduction pathways are involved in agonist-induced EP4 externalization. Agonist-enhanced EP4 externalization increases EP4 cell surface abundance and activity, thus enhancing nociceptor sensitization. SIGNIFICANCE: , CaKMII, cAMP, PKA, PKC, PKCε, PLC, MAPK, PI3K and Akt are involved in this event. Agonist-induced EP4 externalization contributes to enhanced nociceptor sensitization.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. 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.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
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.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".