Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating
Bibliographic record
Abstract
Voltage gating of hyperpolarization-activated cation (HCN) channels is potentiated by direct binding of cAMP to a cytoplasmic cAMP-sensing domain (CSD). When unliganded, the CSD inhibits hyperpolarization-dependent opening of the HCN channel gate; cAMP binding relieves this autoinhibition so that opening becomes more favorable thermodynamically. This autoinhibition-relief mechanism is conserved with that of several other cyclic nucleotide receptors using the same ligand-binding fold. Besides its thermodynamic effect, cAMP also modulates the depolarization-dependent deactivation rate by kinetically trapping channels in an open state. Here we report studies of strong open-state trapping in an HCN channel showing that the well-established autoinhibition-relief model is insufficient. Whereas deletion of the CSD mimics the thermodynamic open-state stabilization usually associated with cAMP binding, CSD deletion removes rather than mimics the kinetic effect of strong open-state trapping. Substitution of different CSD sequences leads to variation of the degree of open-state trapping in the liganded channel but not in the unliganded channel. CSD-dependent open-state trapping is observed during a voltage-dependent deactivation pathway, specific to the secondary open state that is formed by mode shift after prolonged hyperpolarization activation. This hysteretic activation-deactivation cycle is preserved by CSD substitution, but the change in deactivation kinetics of the liganded channel resulting from CSD substitution is not correlated with the change in autoinhibition properties. Thus the liganded and the unliganded forms of the CSD respectively provide the structural determinants for open-state trapping and autoinhibition, such that two distinct mechanisms for cAMP regulation can operate in one receptor.
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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) | 0.000 | 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 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".