Tonic plasma membrane association increases the function of RGS proteins as inhibitors of M1 muscarinic receptor signaling
Bibliographic record
Abstract
RGS2 is a more potent attenuator of M1 muscarinic receptor signaling than other small RGS proteins. To explain differences, the function of RGS2 and RGS5 were compared in HEK293 cells stably expressing the M1 muscarinic receptor. Results show that the carboxyl terminal GAP domains of RGS2 and RGS5 show comparable inhibitory function. Plasma membrane‐targeted RGS GAP domains show enhanced function relative to non‐targeted proteins suggesting that membrane association is a determinant of M1 muscarinic receptor inhibition. Amino terminal domain swaps of RGS2 and RGS5 reveal that the RGS2 amino terminus is sufficient to confer increased plasma membrane association and function. Mutation of a single hydrophobic residue in the amino terminal amphipathic helix of RGS2 and the RGS2/5 chimera reduce their plasma membrane association and inhibitory function without disrupting interaction with the third intracellular loop of the M1 muscarinic receptor. Replacement of two unique leucine residues adjacent to the amphipathic helix of RGS2 with the corresponding residues from RGS5 disrupts membrane localization and function. Together, these data suggest that the amphipathic alpha helix in RGS2 displays an elongated hydrophobic surface that facilitates its increased tonic plasma membrane targeting and greater inhibition of M1 muscarinic signaling relative to RGS5.
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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".