Stimulation of GLP-1 secretion downstream of the ligand-gated ion channel TRPA1

Diabetes. 2015 Apr;64(4):1202-10. doi: 10.2337/db14-0737. Epub 2014 Oct 16.

Abstract

Stimulus-coupled incretin secretion from enteroendocrine cells plays a fundamental role in glucose homeostasis and could be targeted for the treatment of type 2 diabetes. Here, we investigated the expression and function of transient receptor potential (TRP) ion channels in enteroendocrine L cells producing GLP-1. By microarray and quantitative PCR analysis, we identified trpa1 as an L cell-enriched transcript in the small intestine. Calcium imaging of primary L cells and the model cell line GLUTag revealed responses triggered by the TRPA1 agonists allyl-isothiocyanate (mustard oil), carvacrol, and polyunsaturated fatty acids, which were blocked by TRPA1 antagonists. Electrophysiology in GLUTag cells showed that carvacrol induced a current with characteristics typical of TRPA1 and triggered the firing of action potentials. TRPA1 activation caused an increase in GLP-1 secretion from primary murine intestinal cultures and GLUTag cells, an effect that was abolished in cultures from trpa1(-/-) mice or by pharmacological TRPA1 inhibition. These findings present TRPA1 as a novel sensory mechanism in enteroendocrine L cells, coupled to the facilitation of GLP-1 release, which may be exploitable as a target for treating diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Enteroendocrine Cells / cytology
  • Enteroendocrine Cells / metabolism*
  • Glucagon-Like Peptide 1 / metabolism*
  • Intestine, Small / cytology
  • Intestine, Small / metabolism*
  • Mice
  • Mice, Knockout
  • Signal Transduction / physiology*
  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels / genetics
  • Transient Receptor Potential Channels / metabolism*

Substances

  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • Glucagon-Like Peptide 1
  • Calcium