Mechanisms regulating the dopamine D1‐D2 receptor heteromeric signaling complex
Bibliographic record
Abstract
We previously identified that co‐activation of a Gq‐linked heteromeric D1‐D2 dopamine receptor signaling complex results in phospholipase C (PLC)‐dependent intracellular Ca 2+ release. We have demonstrated agonist specificity for the D1‐D2 triggered Ca 2+ signal and the D1 stimulated cyclic AMP production with three D1 agonists, SKF83959, SKF81297, and SKF83822 that differentially activate either the adenylate cyclase (AC) or PLC pathway. Because the three agonists can activate different signaling pathways, we propose that they are effective pharmacological tools for assessing the mechanisms regulating the D1‐D2 signaling complex. Pretreatment of D1‐D2 expressing cells with each agonist lead to 60% desensitization of the Ca 2+ signal within 5 minutes. Intriguingly, occupancy of the D1 binding pocket by SKF 83822 that could not activate the D1‐D2 complex still permitted desensitization of the Ca 2+ response. Results from co‐application of the agonists with a D1 or D2 specific antagonist, suggest the desensitization elicited by each agonist is through selective occupancy of the D1 receptor. Furthermore, over‐expression of wild type G‐protein receptor kinase 2 (GRK2) and its catalytically inert construct, but not its regulator of G‐protein signaling (RGS) domain impaired construct, decreased the Ca 2+ signal, suggesting the RGS domain of GRK2 is involved in regulating the D1‐D2 receptor signaling cascade. This work is supported by the NIH National Institute on Drug Abuse
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 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".