Serine 225 phosphorylation governs the localization and function of sphingosine kinase 1 in resistance arteries
Bibliographic record
Abstract
Sphingosine kinase 1 (Sk1), which synthesizes the vasoconstrictor sphingosine‐1‐phosphate (S1P), must translocate from the cytosol to the plasma membrane in order to access its substrate. We aimed to characterize the serine 225 phosphorylation motif as the molecular switch that regulates the pressure‐dependent activation/translocation of Sk1 in hamster gracilis muscle resistance arteries. Pressure elevation stimulated the phosphorylation of ERK1/2, an upstream activator of Sk1, and the translocation of Sk1 to the plasma membrane. Functionally, preventing Sk1 activation, either by the expression of a non‐phosphorylatable mutant (Sk1 S225A ) or by ERK1/2 inhibition, reduced resting and myogenic tone, resting Ca 2+ , pressure‐induced Ca 2+ elevation and Ca 2+ sensitivity. The effects of Sk1 S225A expression on Ca 2+ were restored by forcing its localization to the plasma membrane, but all other parameters remained inhibited. Forcing wild‐type Sk1 to the plasma membrane inhibited the same parameters. These discrete effects are consistent with cell surface receptor‐mediated effects and intracellular effects of S1P. Accordingly, S1P 2 receptor inhibition attenuated myogenic tone without effect on Ca 2+ . We conclude that: (i) translocation and precise subcellular positioning of Sk1 is essential for full Sk1 function; and (ii) two distinct S1P pools contribute to the maintenance of vascular tone.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".