Intracellular Signaling of Lipid Mediators via Cognate Nuclear G Protein–Coupled Receptors
Bibliographic record
Abstract
Platelet-activating factor (PAF) and lysophosphatidic acid (LPA) are ubiquitous lipid mediators that play important roles in inflammation, cardiovascular homeostasis, and immunity and are also known to modulate gene expression of specific proinflammatory genes. The mechanism of action of these phospholipids is thought to be primarily dependent on their specific plasma membrane receptors belonging to the superfamily of G protein-coupled receptors (GPCRs). However, increasing evidence suggests the existence of a functional intracellular GPCR population. It has been suggested that immediate effects are mediated by cell surface receptors, whereas long-term responses are mediated by intracellular receptors. PAF and LPA(1) receptors localize at the cell nucleus of cerebral microvascular endothelial cells of newborn pig, rat hepatocytes, and cells overexpressing each receptor, and stimulation of isolated nuclei reveal biological functions, including transcriptional regulation of major genes, namely cylooxygenase-2 and inducible nitric oxide synthase. This mini review focuses on the nuclear localization and signaling of GPCRs, recognizing PAF and LPA phospholipids as ligands. Theories on how nuclear PAF and LPA1 receptors activate gene transcription and nuclear localization pathways are discussed. Intracrine signaling for lipid mediators uncover novel pathways to elicit their effects; moreover, intracellular GPCRs constitute a distinctive mode of action for gene regulation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.004 |
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 source (direct Gemma or distilled Codex), 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".