Differential Contribution of G‐protein Coupled Receptor Kinase 2 and 3 in Regulating Structurally Related Human Dopamine D1 and D5 Receptors
Bibliographic record
Abstract
Dopamine (DA) D1‐like receptors (D1R and D5R) are seven‐transmembrane proteins regulating important brain and peripheral functions. Impairment in D1‐like responsiveness may play a crucial role in the phenotypic expression of several brain disorders such as schizophrenia and Parkinson's disease. Agonist‐induced receptor phosphorylation mediated by G‐protein coupled receptor kinase isoforms (GRK1–GRK6) curtails G‐protein signaling and target receptors for internalization. Here we investigated the role of GRK2 and GRK3 in regulating D1R and D5R desensitization in a subtype‐specific manner. Human embryonic kidney 293 cells expressing the D1R or D5R alone or with either GRK2 or GRK3 were analyzed for DA‐mediated receptor activation using whole cell cAMP assays. We demonstrate that GRK2 shows little effect in promoting desensitization of D1R and D5R, whereas GRK3 promotes a significantly more robust desensitization of D1R than D5R as assessed by the extent of DA‐induced maximal stimulation of adenylyl cyclase. However, expression of GRK2 and GRK3 leads to a more reduced DA potency for D5R than for D1R. These findings point to the existence of marked differences in the ability of GRKs to promote D1R and D5R desensitization. Our studies thus provide insight into potential distinct GRK2 and GRK3 molecular mechanisms through which D1‐like receptor signaling is regulated. Supported by a CIHR grant (MOP‐81341) to MT.
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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 | 0.000 |
| 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 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".