Abstract 218: TRPM7 Kinase - A Novel Signaling Pathway for Ang II-induced MAPK Activation in Vascular Smooth Muscle Cells.
Bibliographic record
Abstract
Transient receptor potential melastatin 7 (TRPM7) cation channel is a unique protein, which regulates transmembrane magnesium (Mg2+) transport through its channel domain, and intracellular signaling through its kinase domain. We previously demonstrated that TRPM7, is expressed on vascular smooth muscle cells (VSMC), controls Mg2+ influx, and is regulated by angiotensin II (Ang II). Low Mg2+ levels are among the many factors leading to hypertension, where intracellular Mg2+ deficiency and TRPM7 downregulation is observed. Despite the advancement in the understanding of Mg2+ and TRPM7 biology, the role of TRPM7, and its kinase, in hypertension remains elusive. In this study, we investigated whether deletion of TRPM7 kinase domain alters Ang II-induced Mg2+ influx and signaling in VSMCs. Cultured VSMCs from mesenteric arteries obtained from heterozygous mice for the TRPM7 kinase deletion (+/-) and WT mice were used. Mg2+ influx was assessed by fluorescence microscopy. Activation of MAP kinases was evaluated by immunoblotting. Ang II (10-7M) increase in Mg2+ influx was similar in VSMC from both, WT and TRPM7+/- mice (2.5-fold; p<0.001). Ang II increased phosphorylation of JNK (10-fold), p38MAPK (4-fold) and ERK1/2 (6.4-fold) in VSMC from WT mice (p<0.001). Ang II-induced MAPK activation was blunted in TRPM7+/- VSMC. Moreover, Ang II treatment induced PDGF-R (2-fold) and Akt phosphorylation (3-fold) in VSMC from WT mice (p<0.05), an effect that was also blunted in TRPM+/- VSMC. Ang II induced SMAD2/3 activation in VSMC from WT (1.5-fold; p<0.05) and, with a greater extent, TRPM7+/- mice (3.5-fold; p<0.05). To understand whether the blunted effects of Ang II on intracellular signaling in VSMC from TRPM7+/- mice could be attributed to downregulation of Ang II receptors, AT1R and AT2R expression was assessed. No differences in receptor expression were observed between VSMC from WT and TRPM+/-. In conclusion, our findings identify that TRPM7 kinase domain is not necessary for Mg2+ influx, but it seems to be a novel and important player in Ang II-induced signaling in VSMCs.
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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) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".