Different Subtypes of α1-Adrenoceptor Modulate Different K+ Currents via Different Signaling Pathways in Canine Ventricular Myocytes
Bibliographic record
Abstract
Multiple subtypes (alpha1A, alpha1B, and alpha1D) of alpha1-adrenoreceptors (alpha1ARs) co-exist in the heart and mediate a variety of cellular functions. We studied alphaAR modulation of inward rectifier (IK1) and transient outward (Ito) K(+) currents in canine ventricular myocytes. Phenylephrine at 10 microM depressed only Ito without affecting IK1 and at 100 microM inhibited both Ito and IK1. The effect of phenylephrine on Ito was abolished by (+)niguldipine (10 nm) to inhibit alpha1AARs but not by chloroethyclonidine (10 microM) to inactivate alpha1BARs nor by BMY-7378 to antagonize alpha1DARs. In contrast, phenylephrine inhibition of IK1 was reversed only by BMY-7378 (1 nm). PDD (100 nm, phorbol ester activator of protein kinase C (PKC)) simulates and bisindolylmaleimide (50 nm, PKC inhibitor) weakens phenylephrine modulation of Ito but not IK1. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 and inhibitor peptides abolished the effects of phenylephrine on IK1. Enhancement of PKC or CaMKII activities was seen in alpha1aAR- or alpha1dAR-transfected HEK293 cells and in myocytes pretreated with 10 or 100 microM phenylephrine, respectively. Our data suggest that different subtypes of alpha1ARs selectively modulate different cardiac K(+) currents via different signal transduction mechanisms; alpha1AARs mediate Ito regulation via PKC, and alpha1DARs mediate IK1 regulation via CaMKII.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 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".