TRPM3 activation enhances mitochondrial function and provides neuroprotection in adult sensory neurons
Bibliographic record
Abstract
Peripheral neuropathy (PN) affects approximately 50% of the population with diabetes mellitus depending on age and disease severity. It is associated with substantial morbidity and is characterized by induction of pain and loss of sensory function beginning distally in the lower extremities. Recent studies suggest that molecular cascades maintaining mitochondrial function and calcium homeostasis are effective therapeutic targets for diabetic peripheral neuropathy. Interestingly, our lab has recently reported that muscarinic acetylcholine type 1 receptor (M1R) antagonists stimulated neurite outgrowth, in part, by activating Ca2+/calmodulin-dependent protein kinase kinase II (CaMKKII) and mobilization of AMP-activated protein kinase (AMPK). This further augmented mitochondrial function in sensory neurons imparting protection against neuropathy. Transient receptor potential melastatin receptor 3 (TRPM3) is a TRP type cation channel that triggers Ca2+ influx. TRPM3 is quite unique in that it binds calmodulin and is open under high phosphoinositide levels. We hypothesized that opening of TRPM3 could activate CaMKKII and induce neurite outgrowth and may mimic antimuscarinic drug effects. Dorsal root ganglion (DRG) neurons were isolated from adult control and streptozotocin-induced type 1 diabetic male Sprague-Dawley rats. Assessment of neurite outgrowth was performed in response to pregnenolone sulphate (PS) or CIM0216 (specific TRPM3 agonists, respectively). A significant dose-dependent elevation of neurite outgrowth was observed. These TRPM3 agonists also increased AMPK activation and augmented mitochondrial activity. Our investigations towards understanding of TRPM3 activation and its downstream signaling will hopefully lead to potential therapeutic targets against PN.
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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".