Role of PI3 Kinase Gamma in Excitation-Contraction Coupling and Heart Disease
Bibliographic record
Abstract
Class I phosphoinositide 3-kinases (PI3Ks) are enzymes with both protein and lipid kinase activities that have ubiquitous cellular functions. In the heart, subclass IA PI3Ks, PI3K-alpha and beta, regulate cell growth, apoptosis, cell division and cell size, whereas PI3Kgamma, the only member of subclass IB, has been shown to regulate myocardial contractility. Loss of p110gamma, the catalytic subunit of PI3Kgamma, enhances cardiac excitation-contraction coupling by modulating cyclic adenosine monophosphate (cAMP) levels in subcellular domains containing the sarcoplasmic reticulum (SR) leading to increased cAMP-mediated phosphorylation of phospholamban. The ability of p110gamma to modulate cAMP is likely mediated by the protein-protein interactions with the cAMP-degrading enzymes, phosphodiesterases, independent of its lipid kinase activity. PI3Kgamma also plays a key role in modulating the cAMP response and desensitization of beta-adrenergic receptors. Loss of p110gamma gamma leads to acute decompensation and rapid progression into heart failure in response to pathological biomechanical stress while lipid kinase-dead mutants were relatively resistant suggesting that elevated intracellular cAMP (and its secondary effects) is an important predisposing factor for heart failure. The commercial availability of specific PI3Kgamma inhibitors may be used as therapeutic agents in inflammatory and cardiovascular diseases. In this review article, we discuss the key role of PI3Kgamma gamma in regulating cAMP, Ca(2+) cycling, beta-adrenergic signaling and myocardial structure and function in heart disease.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".