Evidence that 5‐HT stimulates intracellular Ca<sup>2+</sup> signalling and activates pannexin‐1 currents in type II cells of the rat carotid body
Bibliographic record
Abstract
Key points 5‐HT is a neuromodulator released from carotid body (CB) chemoreceptor (type I) cells and facilitates the sensory discharge following chronic intermittent hypoxia (CIH). In the present study, we show that, in addition to type I cells, adjacent glial‐like type II cells express functional, ketanserin‐sensitive 5‐HT2 receptors, and their stimulation increases cytoplasmic Ca2+ derived from intracellular stores. In type II cells, 5‐HT activated a ketanserin‐sensitive inward current (I5‐HT) that was similar to that (IUTP) activated by the P2Y2R agonist, UTP. As previously shown for IUTP, I5‐HT was inhibited by BAPTA‐AM and carbenoxolone (5 μm), a putative blocker of ATP‐permeable pannexin (Panx)‐1 channels; IUTP was reversibly inhibited by the specific Panx‐1 mimetic peptide channel blocker, 10Panx peptide. Paracrine stimulation of type II cells by 5‐HT, leading to ATP release via Panx‐1 channels, may contribute to CB excitability, especially in pathophysiological conditions associated with CIH (e.g. obstructive sleep apnoea). Abstract Carotid body (CB) chemoreceptor (type I) cells can synthesize and release 5‐HT and increased autocrine–paracrine 5‐HT2 receptor signalling contributes to sensory long‐term facilitation during chronic intermittent hypoxia (CIH). However, recent studies suggest that adjacent glial‐like type II cells can respond to CB paracrine signals by elevating intracellular calcium (Δ[Ca2+]i) and activating carbenoxolone‐sensitive, ATP‐permeable, pannexin (Panx)‐1‐like channels. In the present study, using dissociated rat CB cultures, we found that 5‐HT induced Δ[Ca2+]i responses in a subpopulation of type I cells, as well as in most (∼67%) type II cells identified by their sensitivity to the P2Y2 receptor agonist, UTP. The 5‐HT‐induced Ca2+ response in type II cells was dose‐dependent (EC50 ∼183 nm) and largely inhibited by the 5‐HT2A receptor blocker, ketanserin (1 μm), and also arose mainly from intracellular stores. 5‐HT also activated an inward current (I5‐HT) in type II cells (EC50 ∼200 nm) that was reversibly inhibited by ketanserin (1–10 nm), the Ca2+ chelator BAPTA‐AM (5 μm), and low concentrations of carbenoxolone (5 μm), a putative Panx‐1 channel blocker. I5‐HT reversed direction at approximately −11 mV and was indistinguishable from the UTP‐activated current (IUTP). Consistent with a role for Panx‐1 channels, IUTP was reversibly inhibited by the specific Panx‐1 mimetic peptide blocker 10Panx (100 μm), although not by its scrambled control peptide (scPanx). Because ATP is an excitatory CB neurotransmitter, it is possible that the contribution of enhanced 5‐HT signalling to the increased sensory discharge during CIH may occur, in part, by a boosting of ATP release from type II cells via Panx‐1 channels.
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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) | 0.002 | 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".