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

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

Author information

1
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
2
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
3
Department of Clinical Sciences, Diabetes and Endocrinology CRC, Skåne University Hospital Malmö, Malmö, Sweden.
4
Integrated Cardio Metabolic Centre, Karolinska Institutet, Huddinge, Sweden.
5
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
6
Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
7
Department of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
8
Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli Naples, Italy.
9
Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
10
CeMM Research Centre for Molecular Medicine, Vienna, Austria.
11
Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.
12
University Clinic for Internal Medicine III, General Hospital Vienna, Vienna, Austria.
13
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria tibor.harkany@meduniwien.ac.at.

Abstract

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

PMID:
28637794
PMCID:
PMC5510001
DOI:
10.15252/embj.201695347
[Indexed for MEDLINE]
Free PMC Article

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