Effects of the antianginal drug, ranolazine, on the brain sodium channel <scp>N</scp>a<sub>V</sub>1.2 and its modulation by extracellular protons
Bibliographic record
Abstract
BACKGROUND AND PURPOSE: Ranolazine is an antianginal drug currently approved for treatment of angina pectoris in the United States. Recent studies have focused on its effects on neuronal channels and its possible therapeutic uses in the nervous system. We characterized how ranolazine affects the brain sodium channel, Na(V)1.2, and how its actions are modulated by low pH. In this way, we further explore ranolazine's potential as an anticonvulsant and its efficacy in conditions like those during an ischaemic stroke. EXPERIMENTAL APPROACH: We performed whole-cell patch-clamp experiments on the voltage-gated sodium channel, Na(V)1.2. Experiments were performed with extracellular solution titrated to either pH 7.4 or pH 6.0 before and after ranolazine perfusion. KEY RESULTS: Ranolazine accelerates onset and slows recovery of fast and slow inactivation. Ranolazine increases the maximum probability of use-dependent inactivation and reduces macroscopic and ramp sodium currents at pH 7.4. pH 6.0 reduced the slowing of fast inactivation recovery and inhibited use-dependent block by ranolazine. In the presence of ranolazine, the time constants of slow inactivation recovery and onset were significantly increased at pH 6.0 relative to pH 7.4 with 100 μM ranolazine. CONCLUSIONS AND IMPLICATIONS: Our work provides novel insights into the modulation of brain sodium channel, Na(V)1.2, by ranolazine. We demonstrate that ranolazine binds Na(V)1.2 in a state-dependent manner, and that the effects of ranolazine are slowed but not abolished by protons. Our results suggest that further research performed on channels with epilepsy-causing mutations may prove ranolazine to be an efficacious therapy.
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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".