Phenylephrine and sustained acidosis activate the neonatal rat cardiomyocyte Na<sup>+</sup>/H<sup>+</sup>exchanger through phosphorylation of amino acids Ser<sup>770</sup>and Ser<sup>771</sup>
Bibliographic record
Abstract
The mammalian Na(+)/H(+) exchanger isoform 1 (NHE1) is a ubiquitously expressed membrane protein that regulates intracellular pH in the myocardium. NHE1 is also important in mediating myocardial hypertrophy, and the blockage of NHE1 activity prevents hypertrophy and reduces ischemia-reperfusion injury in animal models. We recently demonstrated that extracellular-regulated kinase (ERK)-mediated activation of NHE1 occurs during ischemia-reperfusion of the myocardium. To understand the regulation of NHE1 in the myocardium by phosphorylation, we expressed a series of adenoviruses that express wild-type and mutant cDNA for NHE1. All exogenous cDNA for NHE1 had additional mutations [Leu(163)Phe/Gly(174)Ser], which increases NHE1 resistance to EMD-87580 (a specific blocker of NHE1) 100-fold, and allowed the measurement of exogenous NHE1 while inhibiting endogenous NHE1. By examining the effects of a series of mutations of the NHE1 cytosolic region, we determined that the amino acids Ser(770) and Ser(771) were essential for the acute activation of NHE1 activity in rat cardiomyocytes. The specific mutation of either residue prevented the rapid activation of exchanger activity by a sustained intracellular acidosis through ERK-dependent pathways. The same amino acids were critical to phenylephrine-mediated, ERK-dependent activation of NHE1 activity and increased the phosphorylation in intact rat cardiomyocytes. The results demonstrate that both sustained intracellular acidosis and phenylephrine rapidly activate the NHE1 protein in intact cardiac cells through ERK-dependent pathways that act on a common pathway mediated by amino acids Ser(770) and Ser(771) of the cytosolic tail of the protein.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| 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".