The roles of NHE9 in vesicular trafficking and pH regulation
Bibliographic record
Abstract
Alkali cation/proton exchangers (NHE/SLC9A family) are integral membrane transporters involved in both cellular and systemic pH regulation, among other functions. Members of this family share 25-68% protein sequence identity and vary in both their tissue distribution and subcellular localization. The NHE9 isoform is widely-expressed and present in a subset of early and recycling endosomes that are involved in cargo trafficking and signaling. Interestingly, numerous genetic and expression analyses have linked imbalances in NHE9 function to neurodevelopmental conditions, including autism and attention deficit/hyperactivity. Recent experiments indicate that NHE9 co-localizes with the AMPA receptor subunit GRIA1 in vesicles that traffic during long-term synaptic plasticity, a process that is thought to underlie learning and memory. Furthermore, a recent study using autism-associated variants of NHE9 has indicated that decreased NHE9 function leads to vesicular acidification and deficits in cargo trafficking. However, a detailed analysis of all autism-associated variants was not carried out. To this end, we analyzed the subcellular localization of NHE9 and its autism-associated variants, measured transferrin uptake into recycling endosomes by flow cytometry, and determined vesicular pH by fluorescence ratiometric imaging. None of the exogenously-expressed autism-associated variants mislocalized in HeLa or AP-1 cells. In disagreement with a previous report, we found that only the autism-associated variant Ser438Pro presented significant functional deficits. Moreover, we identified several putative interacting proteins of NHE9 by yeast two-hybrid screening of a human brain cDNA library. These data have begun to shed new insight into the mechanisms underlying the regulation of NHE9 and its involvement in neurodevelopmental disorders.
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How this classification was reachedexpand
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 | 0.001 | 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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".