TMEM55A-mediated PI5P signalling regulates alpha cell actin depolymerisation and glucagon secretion
Bibliographic record
Abstract
AIMS/HYPOTHESIS: Diabetes is associated with the dysfunction of glucagon-producing pancreatic islet alpha cells, although the underlying mechanisms regulating glucagon secretion and alpha cell dysfunction remain unclear. While insulin secretion from pancreatic beta cells has long been known to be controlled partly by intracellular phospholipid signalling, very little is known about the role of phospholipids in glucagon secretion. Using patch-clamp electrophysiology and single-cell RNA sequencing, we previously found that expression of PIP4P2 (encoding TMEM55A, a lipid phosphatase that dephosphorylates phosphatidylinositol-4,5-bisphosphate [PIP2] to phosphatidylinositol-5-phosphate [PI5P]) correlates with alpha cell function. We hypothesise that TMEM55A is involved in glucagon secretion and aim to validate the role of TMEM55A and its potential signalling molecules in alpha cell function and glucagon secretion. METHODS: Correlation analysis was generated from the data in www.humanislets.com . Human islets were isolated at the Alberta Diabetes Institute IsletCore. Electrical recordings were performed on dispersed human or mouse islets with scrambled siRNA or si-PIP4P2 (si-Pip4p2 for mouse) transfection. Glucagon secretion was measured using an islet perfusion system with intact mouse islets. TMEM55A activity was measured using an in vitro on-beads phosphatase assay and live-cell imaging. GTPase activity was measured using an active GTPase pull-down assay. Confocal microscopy was used to quantify F-actin intensity using primary alpha cells and alphaTC1-9 cell lines after chemical treatment. RESULTS: channel activity but through a remodelling of cortical F-actin dependent on TMEM55A lipid phosphatase activity, which occurred in response to oxidative stress. TMEM55A- and PI5P-induced F-actin remodelling depends on the inactivation of GTPase and RhoA, instead of Ras-related C3 botulinum toxin substrate 1 or CDC42. CONCLUSIONS/INTERPRETATION: We reveal a novel pathway by which TMEM55A regulates alpha cell exocytosis by controlling intracellular PI5P and the F-actin network.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".