P2Y<sub>1</sub> receptor‐mediated potentiation of inspiratory motor output in neonatal rat <i>in vitro</i>
Bibliographic record
Abstract
Key points The role of metabotropic purinergic receptors (P2YRs) in modulating motor output from the CNS is virtually unknown, despite the fact that many motoneurons, including respiratory motoneurons, express P2YRs. Using rhythmically active brainstem–spinal cord and medullary slice preparations, we demonstrate that compared to the 4th cervical spinal nerve (C4) inspiratory output controlling the diaphragm, P2YR activation is >10 times more efficacious at potentiating the hypoglossal nerve (XII) inspiratory output controlling airway muscles. P2YR potentiation of inspiratory output appears largely mediated by P2Y1R. Whole‐cell recordings from XII motoneurons (MNs) suggest that the P2Y1R‐mediated potentiation of inspiratory synaptic inputs, glutamate currents, and persistent inward currents, results in part from potentiation of a transient receptor potential cation channel, subfamily M, member 4 (TRPM4)‐mediated, calcium‐activated, non‐specific cation current, ICAN. The low sensitivity of phrenic output to P2YR activation questions its physiological significance in modulating diaphragm activity. However, the greater sensitivity of XII MNs, combined with observations that ATP is often co‐released with noradrenaline and that noradrenergic neuron activity decreases in sleep, makes it tempting to speculate that loss of purinergic modulation contributes to state‐dependent reductions in XII MN excitability. Abstract PreBötzinger complex inspiratory rhythm‐generating networks are excited by metabotropic purinergic receptor subtype 1 (P2Y1R) activation. Despite this, and the fact that inspiratory MNs express P2Y1Rs, the role of P2Y1Rs in modulating motor output is not known for any MN pool. We used rhythmically active brainstem–spinal cord and medullary slice preparations from neonatal rats to investigate the effects of P2Y1R signalling on inspiratory output of phrenic and XII MNs that innervate diaphragm and airway muscles, respectively. MRS2365 (P2Y1R agonist, 0.1 mm) potentiated XII inspiratory burst amplitude by 60 ± 9%; 10‐fold higher concentrations potentiated C4 burst amplitude by 25 ± 7%. In whole‐cell voltage‐clamped XII MNs, MRS2365 evoked small inward currents and potentiated spontaneous EPSCs and inspiratory synaptic currents, but these effects were absent in TTX at resting membrane potential. Voltage ramps revealed a persistent inward current (PIC) that was attenuated by: flufenamic acid (FFA), a blocker of the Ca2+‐dependent non‐selective cation current ICAN; high intracellular concentrations of BAPTA, which buffers Ca2+ increases necessary for activation of ICAN; and 9‐phenanthrol, a selective blocker of TRPM4 channels (candidate for ICAN). Real‐time PCR analysis of mRNA extracted from XII punches and laser‐microdissected XII MNs revealed the transcript for TRPM4. MRS2365 potentiated the PIC and this potentiation was blocked by FFA, which also blocked the MRS2365 potentiation of glutamate currents. These data suggest that XII MNs are more sensitive to P2Y1R modulation than phrenic MNs and that the P2Y1R potentiation of inspiratory output occurs in part via potentiation of TRPM4‐mediated ICAN, which amplifies inspiratory inputs.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".