A TRPV1-to-secretagogin regulatory axis controls pancreatic β-cell survival by modulating protein turnover

EMBO J. 2017 Jul 14;36(14):2107-2125. doi: 10.15252/embj.201695347. Epub 2017 Jun 21.


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.

Keywords: Ca2+ signalling; diabetes; endocannabinoid; exocytosis; β‐cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Humans
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Mice, Knockout
  • Proteins / metabolism*
  • Secretagogins / deficiency
  • Secretagogins / metabolism*
  • Single-Cell Analysis
  • TRPV Cation Channels / metabolism*


  • Proteins
  • SCGN protein, human
  • SCGN protein, mouse
  • Secretagogins
  • TRPV Cation Channels
  • TRPV1 protein, human
  • TRPV1 protein, mouse