Journal
EMBO JOURNAL
Volume 36, Issue 14, Pages 2107-2125Publisher
WILEY
DOI: 10.15252/embj.201695347
Keywords
Ca2+ signalling; beta-cell; diabetes; endocannabinoid; exocytosis
Categories
Funding
- Swedish Research Council
- Hjarnfonden
- Novo Nordisk Foundation
- European Research Council [Secret-Cells 2015-AdG-695136]
- Medical University of Vienna
- JDRF [3-SRA-2015-20-Q-R, 17-2011-258]
- European Molecular Biology Organization (long-term fellowship, ALTF) [586-2014]
- EU FP7 (Marie Curie Actions, EMBOCO-FUND) [GA-2012-600394]
- Alzheimers Research UK [ART-EG2009A-1] Funding Source: researchfish
- Novo Nordisk Fonden [NNF17OC0027294, NNF15OC0015964, NNF14OC0010695] Funding Source: researchfish
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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 beta-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 beta-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 beta-cells.
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