Neuronal nitric oxide synthase inhibits store‐operated Ca <sup>2+</sup> entry in cardiomyocytes via S‐nitrosylation of stromal interaction molecule‐1
Bibliographic record
Abstract
Store‐operated Ca 2+ entry (SOCE) mediated by stromal interacting molecule‐1 (STIM1) and Orai1 represents a major route of Ca 2+ entry in mammalian cells. The luminal domain of STIM1 is critical to Ca 2+ sensing, STIM1 oligomerization and SOCE activation. Notably, the luminal domain contains two cysteine sites (Cys49 and Cys56). It is not known if neuronal nitric oxide synthase (nNOS), which is associated to the sarcoplasmic reticulum (SR) membrane, regulates STIM1 oligomerization and SOCE activity in cardiomyocytes via S‐nitrosylation of these cysteine sites. Here, we show that nNOS deficiency or treatment with a nNOS inhibitor L‐VNIO significantly increased SOCE in cardiomyocytes. Further, the Ca 2+ release‐activated Ca 2+ channel current ( I CRAC ) was significantly enhanced in cardiomyocytes treated with L‐VNIO and in nNOS −/− cardiomyocytes. Consistently, STIM1 S‐nitrosylation was significantly decreased in nNOS −/− hearts. Treatment of HEK293 cells co‐expressing YFP‐Orai1 and mCherry‐STIM1 with the NO donor S‐nitrosoglutathione (GSNO) inhibited STIM1 puncta formation and I CRAC . Remarkably, no functional inhibition was observed in cells expressing the Cys49Ser/Cys56Ser STIM1 double mutant. Mechanistically, we found that NO donors caused Cys49 and Cys56‐specific structural changes associated with reduced protein backbone mobility, significantly increased the thermal stability and suppressed Ca 2+ ‐depletion‐dependent oligomerization of the luminal Ca 2+ ‐sensing region of STIM1. Collectively, our data reveal that nNOS inhibits SOCE in cardiomyocytes through NO‐mediated STIM1 S‐nitrosylation which suppresses oligomerization via enhanced luminal domain stability and rigidity. Support or Funding Information Canadian Institutes of Health Research
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.
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 | 0.001 |
| 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".