Mechanisms underlying local Ca<sup>2+</sup> signalling differences between right and left atrial myocytes at normal and increased frequencies
Bibliographic record
Abstract
Abstract Changes in heart rate affect Ca2+ signalling and contractility in ventricular muscle, but the effects on atrial Ca2+ signalling are poorly understood. Here, we explored how increased stimulation frequency affects right atrial (RA) and left atrial (LA) local Ca2+ signalling and underlying cellular mechanisms. We used two‐dimensional confocal Ca2+ imaging, patch clamping, immunocytochemistry and western blotting in isolated rat atrial myocytes. Centripetal Ca2+ waves were common in both RA and LA myocytes. Increasing the stimulation frequency from 1 to 3 Hz reduced local Ca2+ transients in LA but not in RA myocytes. LA myocytes consistently exhibited threefold faster centripetal Ca2+ propagation than RA myocytes. RA myocytes had a faster Ca2+ decay rate at higher frequencies. Most LA myocytes displayed fast release sites in the interior upon depolarization and significant transverse–axial tubules (TATs) that were partly co‐localized with junctophilin‐2, unlike RA myocytes. Increased frequency similarly reduced the Ca2+ current (ICa) in both cell types, but ICa was larger in RA cells. At increased frequencies, sarcoplasmic reticulum (SR) Ca2+ loading and fractional release (FR) remained stable in RA cells, while peripheral SR content and FR decreased in LA cells. RA cells had higher levels of peripheral SERCA2 and protein expressions of phospholamban (PLB) and phosphorylated PLB. Our data and integrative modelling suggest that LA myocytes may contract faster than RA myocytes due to TAT‐associated faster central Ca2+ release. However, LA Ca2+ signalling is more prone to maladaptation to frequency increases due to less effective SR Ca2+ uptake and a smaller trigger ICa. image Key points Changes in heart rate affect Ca2+ signalling and contractility in ventricular muscle, but the effects on atrial Ca2+ signalling are less well understood. Here we determine how increased electrical stimulation frequency affects right (RA) and left atrial (LA) local Ca2+ signalling and underlying cellular mechanisms. We demonstrate that, during depolarization, centripetal Ca2+ propagation occurs approximately threefold faster in LA myocytes compared to RA myocytes possibly due to fast releases in the interior, associated with transverse–axial tubules, and less peripheral sarcoplasmic reticulum Ca2+ pumps. Increasing stimulation frequency more readily compromises peripheral sarcoplasmic reticulum Ca2+ loading in LA myocytes, thereby impairing local Ca2+ releases, unlike in RA myocytes. The lower peripheral density of sarcoplasmic reticulum Ca2+ pumps, along with reduced levels of phospholamban monomer and phosphorylated phospholamban, in LA myocytes compared to RA myocytes underlies the defective Ca2+ signalling adaptation to increased frequency in the left atrium.
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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) | 0.001 | 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".