Evidence for protein kinase involvement in the 5‐HT–[Ca<sup>2+</sup>]<sub>i</sub>–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body
Bibliographic record
Abstract
New Findings What is the central question of this study? The mammalian carotid body (CB) is a peripheral chemoreceptor organ involved in O2 and CO2/H+ homeostasis. Recent studies suggest that 5‐HT, released from CB receptor cells, can stimulate adjacent glial‐like type II cells, leading to an increase in intracellular Ca2+ (Δ[Ca2+]i) and activation of ATP‐permeable pannexin‐1 (Panx‐1) channels. The aim of this study was to elucidate the role of protein kinases in the 5‐HT–[Ca2+]i–Panx‐1 signalling pathway. What is the main finding and its importance? Src family kinase and protein kinase A, acting downstream from Δ[Ca2+]i, played central roles in 5‐HT‐mediated Panx‐1 channel activation. This provides new insight into mechanisms regulating CB excitation, especially in pathophysiological conditions. Abstract Chemoreceptor (type I) cells of the rodent carotid body (CB) synthesize and release several neurotransmitters/neuromodulators, including 5‐hydroxytryptamine (5‐HT), implicated in enhanced CB excitation after exposure to chronic intermittent hypoxia, e.g. sleep apnoea. However, recent studies suggest that 5‐HT can robustly stimulate adjacent glial‐like type II cells via ketanserin‐sensitive 5‐HT2 receptors, leading to intracellular Ca2+ elevation (Δ[Ca2+]i) and activation of ATP‐permeable pannexin‐1 (Panx‐1) channels. Using dissociated rat CB cultures, we investigated the role of protein kinases in the intracellular signalling pathways in type II cells. In isolated type II cells, 5‐HT activated a Panx‐1‐like inward current (I5‐HT) that was reversibly inhibited by the Src family kinase inhibitor PP2 (1 μm), but not by its inactive analogue, PP3 (1 μm). Moreover, I5‐HT was reversibly inhibited (>90%) by H89 (1 μm), a protein kinase A blocker, whereas the protein kinase C blocker GF109203X (2 μm) was largely ineffective. In contrast, the P2Y2R agonist UTP (100 μm) activated Panx‐1‐like currents that were reversibly inhibited (∼60%) by either H89 or GF109203X. Using fura‐2 spectrofluorimetry, the 5‐HT‐induced Δ[Ca2+]i was unaffected by PP2, H89 and GF109293X, suggesting that the kinases acted downstream of the Ca2+ rise. Given that intracellular Ca2+ chelation was previously shown to block receptor‐mediated Panx‐1 current activation in type II cells, these data suggest that CB neuromodulators use overlapping, but not necessarily identical, signalling pathways to activate Panx‐1 channels and release ATP, a CB excitatory neurotransmitter. In conclusion, these studies provide new mechanistic insight into 5‐HT signalling in the CB that has pathophysiological relevance.
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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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".