Humanized anti-P2X4 scFv reduces ATP-induced P2X4 currents and modulates excitability in human DRG neurons
Bibliographic record
Abstract
Chronic pain affects nearly 100 million adults in the U.S., yet few novel therapeutics have emerged in recent decades. P2X4 receptor (P2X4R), implicated in pain signaling, represents a promising target. We evaluated a humanized single-chain variable fragment (hscFv) targeting P2X4R for its ability to reduce ATP-induced currents and modulate excitability in human dorsal root ganglion (hDRG) neurons. Voltage-clamp recordings confirmed that human P2X4R (hP2X4R) hscFv significantly reduced ATP-evoked currents in HEK-293T cells expressing human P2X4, likely by relocalization of the receptor to the perinuclear region after hscFv treatment. Immunohistochemistry and transcriptomic analyses demonstrated widespread P2X4R ( P2RX4 ) expression across hDRG neuronal subtypes in both male and female donors. Current-clamp recordings revealed that hP2X4R hscFv selectively increased action potential (AP) threshold in multi-firing hDRG neurons, without affecting single-firing neurons. Spontaneous activity at rest and depolarizing spontaneous fluctuation (DSF) amplitude were also reduced. Analysis confirmed consistent effects of hP2X4R hscFv on excitability parameters. These findings suggest that hP2X4 hscFv exerts modest but targeted effects on human sensory neurons, supporting its potential as a novel therapeutic for chronic pain.
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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 | 0.000 | 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".