Desensitization of the Dopamine D1‐D2 Receptor Heteromeric Complex in Primary Striatal Neurons and Bi‐functional Regulation by GRK2
Bibliographic record
Abstract
Co‐activation of a Gq‐linked heteromeric D1‐D2 dopamine receptor signaling complex results in phospholipase C‐dependent intracellular calcium release. We have specifically identified that the D1 agonist, SKF83959, selectively activates the D1‐D2 receptor heteromer, while SKF83822 only activates the D1 homooligomer. These agonists were used to evaluate agonist induced desensitization of the D1‐D2 receptor heteromer mediated calcium signal. Pre‐treatment with each agonist for 5 min led to rapid desensitization of the calcium signal both in cells and in primary striatal neurons. Desensitization was abolished by the D1 antagonist, but not by the D2 antagonist. Expression of G protein‐coupled receptor kinase 2 (GRK2) led to a decrease in the calcium signal. This was mediated by both the catalytic and RGS domains of GRK2. Our results indicate that desensitization of the D1‐D2 receptor heteromer mediated calcium signal occurs by D1 receptor occupancy with or without signal activation and is regulated by two distinct functions of GRK2. Intriguingly, occupancy of the D1 receptor binding pocket by SKF83822 that was unable to activate the D1‐D2 receptor complex still permitted desensitization of the calcium response, suggesting that activation of the receptor was not a prerequisite and occupancy of the receptor binding pocket with its associated conformational changes could lead to decreased signaling. 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 | 0.000 | 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".