Tetraspanin‐7 regulation of L‐type voltage‐dependent calcium channels controls pancreatic β‐cell insulin secretion
Bibliographic record
Abstract
Key points Tetraspanin (TSPAN) proteins regulate many biological processes, including intracellular calcium (Ca2+) handling. TSPAN‐7 is enriched in pancreatic islet cells; however, the function of islet TSPAN‐7 has not been identified. Here, we characterize how β‐cell TSPAN‐7 regulates Ca2+ handling and hormone secretion. We find that TSPAN‐7 reduces β‐cell glucose‐stimulated Ca2+ entry, slows Ca2+ oscillation frequency and decreases glucose‐stimulated insulin secretion. TSPAN‐7 controls β‐cell function through a direct interaction with L‐type voltage‐dependent Ca2+ channels (CaV1.2 and CaV1.3), which reduces channel Ca2+ conductance. TSPAN‐7 slows activation of CaV1.2 and accelerates recovery from voltage‐dependent inactivation; TSPAN‐7 also slows CaV1.3 inactivation kinetics. These findings strongly implicate TSPAN‐7 as a key regulator in determining the set‐point of glucose‐stimulated Ca2+ influx and insulin secretion. Abstract Glucose‐stimulated insulin secretion (GSIS) is regulated by calcium (Ca2+) entry into pancreatic β‐cells through voltage‐dependent Ca2+ (CaV) channels. Tetraspanin (TSPAN) transmembrane proteins control Ca2+ handling, and thus they may also modulate GSIS. TSPAN‐7 is the most abundant islet TSPAN and immunostaining of mouse and human pancreatic slices shows that TSPAN‐7 is highly expressed in β‐ and α‐cells; however, the function of islet TSPAN‐7 has not been determined. Here, we show that TSPAN‐7 knockdown (KD) increases glucose‐stimulated Ca2+ influx into mouse and human β‐cells. Additionally, mouse β‐cell Ca2+ oscillation frequency was accelerated by TSPAN‐7 KD. Because TSPAN‐7 KD also enhanced Ca2+ entry when membrane potential was clamped with depolarization, the effect of TSPAN‐7 on CaV channel activity was examined. TSPAN‐7 KD enhanced L‐type CaV currents in mouse and human β‐cells. Conversely, heterologous expression of TSPAN‐7 with CaV1.2 and CaV1.3 L‐type CaV channels decreased CaV currents and reduced Ca2+ influx through both channels. This was presumably the result of a direct interaction of TSPAN‐7 and L‐type CaV channels because TSPAN‐7 coimmunoprecipitated with both CaV1.2 and CaV1.3 from primary human β‐cells and from a heterologous expression system. Finally, TSPAN‐7 KD in human β‐cells increased basal (5.6 mM glucose) and stimulated (45 mM KCl + 14 mM glucose) insulin secretion. These findings strongly suggest that TSPAN‐7 modulation of β‐cell L‐type CaV channels is a key determinant of β‐cell glucose‐stimulated Ca2+ entry and thus the set‐point of GSIS.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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".