Proximity-dependent proteomics and network analysis of adenylyl cyclase isoforms 5, 6, and 9 in cardiomyocytes
Bibliographic record
Abstract
cAMP influences multiple aspects of cardiac biology, including the regulation of contraction, relaxation, and overall stress responses. The functional outcomes of cAMP are driven by the spatial arrangement of enzymes that produce and degrade cAMP (adenylyl cyclase [AC] and phosphodiesterase, respectively), together with the downstream targets of cAMP. We performed proximity-dependent biotin identification (BioID) of near-neighbor interactions proteomics in cardiomyocytes to generate proximity maps for three cardiac AC isoforms. Processing and trafficking functions were the most common gene ontology terms for ACs, with AC5 and AC6 generating unique proximal protein sets compared to AC9. AC5/6 proximal proteins showed significant localization at the endo/sarcoplasmic reticulum with roles in calcium handling, whereas those near AC9 were more abundant at the plasma membrane. Upon treatment with the hypertrophic stimulus norepinephrine, only a few calcium handling proteins were differentially labeled for AC5/6, but not AC9. Endogenous AC activity copurified with vesicle transport, signaling, and muscle contraction proteins that were identified by BioID and/or pulldown of FLAG-tagged AC (FLAG-mass spectrometry) in cardiomyocytes, including ryanodine receptor 2, ATP2A2 (sarco/endoplasmic reticulum Ca 2 + -ATPase 2), epidermal growth factor receptor, syntrophin alpha 1, and vesicle-associated membrane protein 2. Finally, overlapping BioID and FLAG-mass spectrometry datasets suggested heterodimerization of AC5 and AC6, while super-resolution electron microscopy spatial mapping validated homodimerization and heterodimerization of these AC isoforms on the plasma membrane. Overall, our comprehensive network analysis has identified new binding partners and shed light on the spatial and functional significance of AC-containing macromolecular complexes in heart.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".