Regulation of vascular smooth muscle cell function by adenylyl cyclase isoforms
Bibliographic record
Abstract
Adenylyl cyclases (AC), a family of enzymes that catalyze the synthesis of cyclic AMP, are critical regulators of cellular functions. Regulation patterns differ between the AC isoforms, however the consequences of activation of any individual AC isoform (e.g., to catalyze the synthesis of cAMP) were thought to be common to all isoforms. To examine this hypothesis we studied the effect of adenoviral gene transfer of representative AC isoforms AC I, II, V and VI on whole cell cAMP activity, regulation of vascular smooth muscle cell proliferation, isoproterenol (ISO)-mediated arborization responses (an index of cytoskeletal re-organization) and protein kinase A (PKA) activity Although all AC isoforms when expressed in smooth muscle cells comparably enhanced forskolin (FSK)-stimulated cAMP synthesis (186–208% of the AC activity in GFP-infected cells), only AC I-infected cells demonstrated an enhancement of FSK-stimulated inhibition of proliferation (19±3% of GFP, p<0.01). Only gene transfer of AC VI enhanced ISO-mediated arborization (155±16% of GFP, p<0.05). To further examine the contribution of AC VI to the arborization response, we utilized a “knockdown” approach based on expression of a truncated-AC VI dominant negative mutant (TM1T). TM1T expression significantly reduced FSK-stimulated AC activation (79±8% of GFP alone) and ISO-mediated arborization (54±6% of GFP alone). This reduction in arborization was recovered by the co-expression of AC isoform VI (84±10%). Lastly, FSK-stimulated PKA activity was significantly reduced (61±5% of GFP) by AC I expression and significantly enhanced (132±8% of GFP) by AC VI expression. In aggregate these data support a previously unappreciated role for specific AC isoforms in directing the effect of elevation of intracellular cAMP in the regulation of vascular function. Supported by CIHR.
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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".