Modulation of KCNQ Channels is a Potential Mechanism for Controlling Inspiratory Burst Duration
Bibliographic record
Abstract
The preBötzinger Complex (preBötC) is a key site of inspiratory rhythm generation in mammals and significant progress has been made toward defining the mechanisms underlying inspiratory burst generation. In contrast, the mechanisms that control burst duration have received relatively little attention. Here we test the hypotheses that KCNQ channels help determine inspiratory burst duration and contribute to burst termination. KCNQ channels mediate a slow, voltage‐gated outward K + current that is active at resting membrane potential and becomes larger with membrane depolarization. This current helps determine resting membrane potential and also acts to stabilize membrane potential. Using rhythmically‐active brainstem spinal cord (BSSC) and rhythmic medullary slice preparations from neonatal rats (postnatal day 0–4), we examined the role of KCNQ in controlling inspiratory behavior by assessing the effects of KCNQ inhibitors and activators on inspiratory burst duration and inspiratory frequency recorded from the C4 ventral nerve root in BSSC preparations and the XII nerve in slices. Bath application of the KCNQ channel blockers XE991 (0.1 μM and 1 μM) and linopirdine (6 μM, BSSC; 3 μM, slice) caused a time‐ and concentration‐dependent increase in burst duration (XE991, 1 μM: BSSC: 1.35 ± 0.05 fold increase, n = 6, p < 0.05; slice: 3.59 ± 0.20 fold increase, n = 5, p < 0.05; linopirdine: BSSC: 1.22 ± 0.04 fold increase, n = 8, p < 0.05 slice: 1.94 ± 0.13 fold increase, n = 6, p < 0.05), but only XE991 caused a decrease in burst frequency (1 μM: 0.52 ± 0.03 of control levels, p < 0.05). Local microinjection of XE991 (10 μM) directly into the preBötC produced very similar effects on burst duration (3.65 ± 0.86 fold increase, n = 3, p < 0.05) and burst frequency (0.59 ± 0.04 of control, p < 0.05). In contrast, potentiation of the KCNQ current via bath application of retigabine (2 μM) caused a significant decrease in inspiratory burst duration (BSSC: 0.62 ± 0.05 times control, n = 5, p < 0.05; slice: 0.72 ± 0.06 times control, n = 8, p < 0.05) and a decrease in burst frequency. Inspiratory burst generation ceased when retigabine concentration was increased to 3 μM. These data suggest that activation of KCNQ channels specifically within the preBötC contributes to inspiratory burst termination and that their modulation may provide a mechanism for controlling inspiratory burst duration. Funding: CIHR, NSERC, WCHRI, AIHS, CFI. Support or Funding Information CIHR, NSERC, WCHRI, AIHS, CFI
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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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".