Beta-3 Adrenoceptor Signaling Pathways in Urothelial and Smooth Muscle Cells in the Presence of Succinate
Bibliographic record
Abstract
Succinate, an intermediate metabolite of the Krebs cycle, can alter the metabolomics response to certain drugs and controls an array of molecular responses in the urothelium through activation of its receptor, G-protein coupled receptor 91 (GPR91). Mirabegron, a β3-adrenergic receptor (β3-AR) agonist used to treat overactive bladder syndrome (OAB), increases intracellular cAMP in the detrusor smooth muscle cells (SMC), leading to relaxation. We have previously shown that succinate inhibits forskolin-stimulated cAMP production in urothelium. To determine whether succinate interferes with mirabegron-mediated bladder relaxation, we examined their individual and synergistic effect in urothelial-cell and SMC signaling. We first confirmed β3-AR involvement in the mirabegron response by quantifying receptor abundance by immunoblotting in cultured urothelial cells and SMC and cellular localization by immunohistochemistry in rat bladder tissue. Mirabegron increased cAMP levels in SMC but not in urothelial cells, an increase that was inhibited by succinate, suggesting that it impairs cAMP-mediated bladder relaxation by mirabegron. Succinate and mirabegron increased inducible nitric oxide synthesis and nitric oxide secretion only in urothelial cells, suggesting that its release can indirectly induces SMC relaxation. Succinate exposure decreased the expression of β3-AR protein in whole bladder in vivo and in SMC in vitro, indicating that this metabolite may lead to impaired pharmacodynamics of the bladder. Together, our results demonstrate that increased levels of succinate in settings of metabolic stress (e.g., the metabolic syndrome) may lead to impaired mirabegron and β3-AR interaction, inhibition of cAMP production, and ultimately requiring mirabegron dose adjustment for its treatment of OAB related to these conditions.
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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".