Differential signaling of dopamine‐D<sub>2</sub>S and ‐D<sub>2</sub>L receptors to inhibit ERK1/2 phosphorylation
Bibliographic record
Abstract
Although they have distinct functions, the signaling of dopamine-D(2) receptor short and long isoforms (D(2)S and D(2)L) is virtually identical. We compared inhibitory regulation of extracellular signal-regulated kinases (ERK1/2) in GH4 pituitary cells separately transfected with these isoforms. Activation of rat or human dopamine-D(2)S, muscarinic or somatostatin receptors inhibited thyrotropin-releasing hormone-induced ERK1/2 phosphorylation, while the D(2)L receptor failed to inhibit this response. In order to address the structural basis for the differential signaling of D(2)S and D(2)L receptors, we examined the D(2)L-SS mutant, in which a protein kinase C (PKC) pseudosubstrate site that is present in the D(2)L but not D(2)S receptor was converted to a consensus PKC site. In transfected GH4 cells, the D(2)L-SS mutant inhibited thyrotropin-releasing hormone-induced ERK1/2 phosphorylation almost as strongly as the D(2)S receptor. A D(2)S-triple mutant that eliminates PKC sites involved in D(2)S receptor desensitization also inhibited ERK1/2 activation. Similarly, in striatal cultures, the D(2)-selective agonist quinpirole inhibited potassium-stimulated ERK1/2 phosphorylation, indicating the presence of this pathway in neurons. In conclusion, the D(2)S and D(2)L receptors differ in inhibitory signaling to ERK1/2 due to specific residues in the D(2)L receptor alternatively spliced domain, which may account for differences in their function in vivo.
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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) | 0.000 | 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) | 0.000 | 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".