Activation of Adenosine Triphosphate-Sensitive Potassium Channels by Acyl Coenzyme A Esters Involves Multiple Phosphatidylinositol 4,5-Bisphosphate-Interacting Residues
Bibliographic record
Abstract
ATP-sensitive potassium (K(ATP)) channels are crucial to pancreatic endocrine function and their activation by acyl coenzyme A esters (acyl CoAs) may disrupt hormone secretion, contributing to the pathophysiology of type 2 diabetes. The molecular mechanism of this activation is potentially important in our further understanding of this disease. We use excised patch-clamp techniques to assess the effects of N- and C-terminal Kir6.2 mutations on the activation of recombinant K(ATP) channels by palmitoyl CoA. We demonstrate that several residues previously shown to be involved in channel activation by the structurally related lipid phosphatidylinositol 4,5-bisphosphate (PIP(2)) also play a role in activation by acyl CoAs, including R54, R176, R192, and R301. Mutation of these residues caused decreased open probability in the absence of ATP and slower and greater relative activation by both PIP(2) and acyl CoAs. By contrast, K185Q, which probably alters ATP binding, had no effect on either PIP(2) or palmitoyl CoA activation. These findings suggest that activation by the two classes of lipids involves multiple common residues. We use the crystal structure of a related channel, KirBac1.1, as a template to locate the residues of interest in this study within a putative three-dimensional model of Kir6.2. We propose a model in which these residues mediate both direct electrostatic interactions and allosteric modulations of open state stability.
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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 | 0.001 |
| 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".