Ca2+-Handling Proteins and Heart Failure: Novel Molecular Targets?
Bibliographic record
Abstract
Calcium (Ca(2+)) ions are the currency of heart muscle activity. During excitation-contraction coupling Ca(2+) is rapidly cycled between the cytosol (where it activates the myofilaments) and the sarcoplasmic reticulum (SR), the Ca(2+) store. These fluxes occur by the transient activity of Ca(2+)-pumps and -channels. In the failing human heart, changes in activity and expression profile of Ca(2+)-handling proteins, in particular the SR Ca(2+)-ATPase (SERCA2a), are thought to cause an overall reduction in the amount of SR-Ca(2+) available for contraction. In the steady state, the Ca(2+)-content of the SR is essentially a balance between Ca(2+)-uptake via SERCA2a pump and Ca(2+)-release via the cardiac SR Ca(2+)-release channel complex (Ryanodine receptor, RyR2). This review discusses current pharmacological options available to enhance cardiac SR Ca(2+) content and the implications of this approach as an inotropic therapy in heart failure. Two options are considered: (i) activation of the SERCA2a pump to increase SR Ca(2+)-uptake, and (ii) reduction of SR Ca(2+)-leakage through RyR2. RyR2 forms a macromolecular complex with a number of regulatory proteins that either remain permanently bound or that interact in a time- and/or Ca(2+)-dependant manner. These regulatory proteins can dramatically affect RyR2 function, e.g. over-expression of the accessory protein FK 506-binding protein 12.6 (FKBP12.6) has recently been shown to reduce SR Ca(2+)-leak. Recent attempts to design positive inotropes for chronic administrations have focussed on the use of phosphodiesterase III inhibitors (PDE III inhibitors). These compounds, which increase intracellular cAMP-levels, have failed in clinical trials. Therefore medical researchers are seeking new drugs that act through alternative pathways. Novel cardiac inotropes targeting SR Ca(2+)-cycling proteins may have the potential to fill this gap.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| 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 | 0.001 | 0.002 |
| 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".