Functional Signatures of α‐7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulators: Effects on Channel Biophysics and Pharmacology.
Bibliographic record
Abstract
Activation of neuronal α7 nicotinic acetylcholine receptors by agonists evokes rapidly activating, desensitizing currents, predominantly carried by Na + and Ca 2+ ions. Positive allosteric modulators (PAMs) of α7 nAChRs are devoid of intrinsic agonist activity but enhance α7 currents with or without effects on channel kinetics. Using patch clamp and Ca 2+ flux assays in GH4C1 cells heterologoulsly expressing rat α7 receptors we describe the mechanism of action of α7 PAMs and their modulation by changes in temperature and repeat applications. All PAMs enhanced the current amplitude. Additionally the type‐2 PAMs also slowed channel desensitization. We show that PNU‐120596, a type‐2 PAM exhibited reduced potentiation of current amplitude upon repeated applications with no change in the EC50 of activation. PNU‐120596 also "dedesensitizes" receptors fully desensitized by exposure to high concentrations of agonists. NS‐1738, a type‐1 PAM exhibited a modest decrease in maximal current amplitude upon repeated application accompanied with 3‐fold increase in potency. SB‐206553 a type‐1/2 PAM did not exhibit differences in the extent of current amplitude potentiation or pharmacology upon repeated application. Modulatory effects of PAMs, though significant at room temperature, were attenuated near physiological temperatures. Furthermore, PNU‐120596 but not SB‐206553 largely removed the strong inward rectification usually exhibited by α7 nAChR receptor agonists.
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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".