Cdk5 regulates IP3R1-mediated Ca2+ dynamics and Ca2+-mediated cell proliferation
Bibliographic record
Abstract
Abstract Loss of cyclin-dependent kinase 5 (Cdk5) in the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) increases ER–mitochondria tethering and ER Ca 2+ transfer to the mitochondria, subsequently increasing mitochondrial Ca 2+ concentration ([Ca 2+ ] mt ). This suggests a role for Cdk5 in regulating intracellular Ca 2+ dynamics, but how Cdk5 is involved in this process remains to be explored. Using ex vivo primary mouse embryonic fibroblasts (MEFs) isolated from Cdk5 −/− mouse embryos, we show here that loss of Cdk5 causes an increase in cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ), which is not due to reduced internal Ca 2+ store capacity or increased Ca 2+ influx from the extracellular milieu. Instead, by stimulation with ATP that mediates release of Ca 2+ from internal stores, we determined that the rise in [Ca 2+ ] cyt in Cdk5 −/− MEFs is due to increased inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca 2+ release from internal stores. Cdk5 interacts with the IP3R1 Ca 2+ channel and phosphorylates it at Ser 421 . Such phosphorylation controls IP3R1-mediated Ca 2+ release as loss of Cdk5, and thus, loss of IP3R1 Ser 421 phosphorylation triggers an increase in IP3R1-mediated Ca 2+ release in Cdk5 −/− MEFs, resulting in elevated [Ca 2+ ] cyt . Elevated [Ca 2+ ] cyt in these cells further induces the production of reactive oxygen species (ROS), which upregulates the levels of Nrf2 and its targets, Prx1 and Prx2. Cdk5 −/− MEFs, which have elevated [Ca 2+ ] cyt , proliferate at a faster rate compared to wt, and Cdk5 −/− embryos have increased body weight and size compared to their wt littermates. Taken together, we show that altered IP3R1-mediated Ca 2+ dynamics due to Cdk5 loss correspond to accelerated cell proliferation that correlates with increased body weight and size in Cdk5 −/− embryos.
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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) | 0.002 | 0.001 |
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".