| Autor: |
Malenczyk, Katarzyna, Girach, Fatima, Szodorai, Edit, Storm, Petter, Segerstolpe, Åsa, Tortoriello, Giuseppe, Schnell, Robert, Mulder, Jan, Romanov, Roman A, Borók, Erzsébet, Piscitelli, Fabiana, Di Marzo, Vincenzo, Szabó, Gábor, Sandberg, Rickard, Kubicek, Stefan, Lubec, Gert, Hökfelt, Tomas, Wagner, Ludwig, Groop, Leif, Harkany, Tibor |
| Předmět: |
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| Zdroj: |
EMBO Journal; 7/14/2017, Vol. 36 Issue 14, p2107-2125, 19p, 7 Graphs |
| Abstrakt: |
Ca2+-sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single-cell RNA-seq reveals retained expression of the TRP family members in β-cells from diabetic donors. Amongst these, pharmacological probing identifies Ca2+-permeable transient receptor potential vanilloid type 1 channels ( TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV1s fails to rescue insulin release from pancreatic islets of glucose intolerant secretagogin knock-out(−/−) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin−/− mice is due to β-cell loss, which is underpinned by the collapse of protein folding and deregulation of secretagogin-dependent USP9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV1s in diabetic pancreata, a TRPV1-to-secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of β-cells. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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