TRUSS, TNF‐R1, and TRPC ion channels synergistically reverse endoplasmic reticulum Ca<sup>2+</sup> storage reduction in response to m1 muscarinic acetylcholine receptor signaling
Bibliographic record
Abstract
Although most signaling responses initiated by tumor necrosis factor-alpha (TNF-alpha) occur in a Ca(2+)-independent fashion, TNF-alpha receptor signaling augments Ca(2+) entry induced by Galpha(q/11) G-protein coupled receptors (GPCRs) in endothelial cells and increases trans-endothelial permeability. The signaling events involved in GPCR-induced Ca(2+) influx have been characterized and involve store-operated Ca(2+) entry facilitated by the Ca(2+) permeable ion channel, transient receptor potential canonical 4 (TRPC4). Little is known about the mechanisms by which TNF-alpha receptor signaling augments GPCR-induced Ca(2+) entry. TNF-alpha Receptor Ubiquitous Signaling and Scaffolding protein (TRUSS) is a tumor necrosis factor receptor-1 (TNF-R1)-associated protein whose gene name is TRPC4-associated protein (TRPC4AP). The goal of our study was to test the hypothesis that TRUSS serves to link TNF-R1 and GPCR-signaling pathways at the level of TRPC4 by: (i) determining if TRUSS and TNF-R1 interact with TRPC4, and (ii) investigating the role of TRUSS, TNF-R1, and TRPC4 in GPCR-induced Ca(2+) signaling. Here, we show that TRUSS and TNF-R1 interact with a sub-family of TRPC channels (TRPC1, 4, and 5). In addition, we show that TRUSS and TNF-R1 function together with TRPC4 to elevate endoplasmic reticulum Ca(2+) filling in the context of reduced endoplasmic reticulum Ca(2+) storage initiated by G-protein coupled m1 muscarinic acetylcholine receptor (m1AchR) signaling. Together, these findings suggest that TNF-R1, TRUSS, and TRPC4 augment Ca(2+) loading of endoplasmic reticulum Ca(2+) stores in the context of m1AchR stimulation and provide new insights into the mechanisms that connect TNF-R1 to GPCR-induced Ca(2+) signaling.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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".