2-B-174 - Amyloid beta oligomers sensitizes Panx1 activation by NMDAR via ER resident STIM proteins
Bibliographic record
Abstract
Authors: Chetan Patil¹, Natalie Lavine¹, Michael Jackson¹ ¹University of Manitoba Abstract: Loss of Ca2+ homeostasis is a key neurotoxic event underlying Alzheimer's disease pathology. Herein, amyloid-β oligomers (AβOs) provoke aberrant activation of Ca2+ permeable NMDA receptor (NMDARs) and sensitize Ca2+ release through endoplasmic reticulum (ER). Altered ER Ca2+ release dynamics caused by AβOs is sensed by the stromal interacting molecules (STIMs), which are known to activate surface expressed Ca2+ permeable channels through protein-protein interactions. Past studies have shown that overactivation of NMDARs activate pannexin1 (Panx1) channels. We now show that Panx1 activation is augmented by AβOs. Cultured hippocampal neurons from CD1, Panx1 WT and Panx1 KO mice were used for electrophysiological recordings. First, we show that excitatory synaptic deficits induced by AβOs require Panx1. Moreover, Panx1 activation by NMDARs, facilitated by AβO treatment, is reduced in STIM knockdown neurons. To establish the mechanism of Panx1 activation by STIM, we generated Panx1 mutants with deletions targeting intracellular N- and C-term domains. Our results show that a domain within the N-term of Panx1 is required for activation by STIM. Further, NMDAR-dependent Panx1 activation was eliminated in cultured neurons expressing a Panx1 mutant unable to bind STIMs. To conclude, our study is first to report the importance of the Panx1-STIM interaction in regulating activity of Panx1 channels downstream of NMDARs. Future investigations aim to develop potential therapeutic targets within our discovered region to modulate Panx1 activity and impede detrimental effects of AβOs.
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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) | 0.003 | 0.001 |
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".