2-B-174 - Amyloid beta oligomers sensitizes Panx1 activation by NMDAR via ER resident STIM proteins
Why this work is in the frame
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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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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.060 | 0.013 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.002 | 0.006 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.003 | 0.000 |
| Open science | 0.003 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.038 | 0.002 |
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 it