Ser/ Thr residues at α3/β5 loop of Gαs are important in morphine‐induced adenylyl cyclase sensitization but not mitogen‐activated protein kinase phosphorylation
Bibliographic record
Abstract
The signaling switch of β2-adrenergic and μ(1) -opioid receptors from stimulatory G-protein (G(αs) ) to inhibitory G-protein (G(αi) ) (and vice versa) influences adenylyl cyclase (AC) and extracellular-regulated kinase (ERK)1/2 activation. Post-translational modifications, including dephosphorylation of G(αs) , enhance opioid receptor coupling to G(αs) . In the present study, we substituted the Ser/Thr residues of G(αs) at the α3/β5 and α4/β6 loops aiming to study the role of G(αs) lacking Ser/Thr phosphorylation with respect to AC sensitization and mitogen-activated protein kinase activation. Isoproterenol increased the cAMP concentration (EC(50) = 22.8 ± 3.4 μm) in G(αs) -transfected S49 cyc- cells but not in nontransfected cells. However, there was no significant difference between the G(αs) -wild-type (wt) and mutants. Morphine (10 μm) inhibited AC activity more efficiently in cyc- compared to G(αs) -wt introduced cells (P < 0.05); however, we did not find a notable difference between G(αs) -wt and mutants. Interestingly, G(αs) -wt transfected cells showed more sensitization with respect to AC after chronic morphine compared to nontransfected cells (101 ± 12% versus 34 ± 6%; P < 0.001); μ1-opioid receptor interacted with G(αs) , and both co-immunoprecipitated after chronic morphine exposure. Furthermore, mutation of T270A and S272A (P < 0.01), as well as T270A, S272A and S261A (P < 0.05), in α3/β5, resulted in a higher level of AC supersensitization. ERK1/2 phosphorylation was rapidly induced by isoproterenol (by 9.5 ± 2.4-fold) and morphine (22 ± 2.2-fold) in G(αs) -transfected cells; mutations of α3/β5 and α4/β6 did not affect the pattern or extent of mitogen-activated protein kinase activation. The findings of the present study show that G(αs) interacts with the μ1-opioid receptor, and the Ser/Thr mutation to Ala at the α3/β5 loop of G(αs) enhances morphine-induced AC sensitization. In addition, G(αs) was required for the rapid phosphorylation of ERK1/2 by isoproterenol but not morphine.
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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) | 0.002 | 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".