Targeting adenylyl cyclase isoform 6: novel therapy for pulmonary hypertension
Bibliographic record
Abstract
<bold>Introduction:</bold> Intracellular second messenger cAMP is synthesized by adenylyl cyclases (AC1-9), all allosterically activated by forskolin (FSK). AC selective drugs are not available. We discovered that hypoxia induces S-nitrosylation of AC6 in pulmonary artery (PA) myocytes, at critical residue C1004 at the AC6-Gαs interface, resulting in AC6 inhibition and pulmonary hypertension. We hypothesized that novel FSK derivatives selectively targeting AC6 could rescue hypoxic inhibition. <bold>Methods:</bold> PA myocytes from neonatal swine; HEK293 cells expressing PA AC isoforms AC3, 5, 6, 7 or 9; and AC6 cysteine-to-alanine mutants (AC6_C1004A, AC6_C1145A, AC6_C447A) were cultured in normoxia (21% O2) or hypoxia (10% O2) for 72 hours, or treated with nitroso donor S-nitrosocysteine (CysNO). AC catalytic activity and S-nitrosylation were measured in cell lysates; FSK-induced cAMP production quantified by live-cell biosensor. A library of forskolin derivatives was synthesized and evaluated for isoform-selective AC activation; functional efficacy was validated in PA by isometric myography. <bold>Results:</bold> Among AC isoforms, only AC6 catalytic activity is inhibited by hypoxia or by CysNO; decreased cAMP production correlates with increased S-nitrosylation of AC6. Selective AC6 inhibition in PA myocytes abolishes hypoxic AC inhibition. Mutation of C1004 to alanine decreases AC6 S-nitrosylation and eliminates hypoxia sensitivity of AC6. Among tested compounds, a FSK carbonate derivative exhibited AC6 selectivity, rescuing AC6 activity. <bold>Conclusion:</bold> Hypoxia inhibits AC6 activity, but FSK rescues its function even under hypoxic conditions. Selective AC6 reactivation is a promising therapeutic strategy for hypoxic pulmonary hypertension.
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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".