title: Stimulation of GLP-1 secretion downstream of the ligand-gated ion channel TRPA1.
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.
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Emery
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Diakogiannaki
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, U.K.
authors.forename: Clive
authors.initials: C
authors.lastname: Gentry
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Arianna
authors.initials: A
authors.lastname: Psichas
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, U.K.
authors.forename: Abdella M
authors.initials: AM
authors.lastname: Habib
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, U.K.
authors.forename: Stuart
authors.initials: S
authors.lastname: Bevan
authors.affiliation: Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Michael J M
authors.initials: MJ
authors.lastname: Fischer
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, U.K. fmg23@cam.ac.uk fr222@cam.ac.uk.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, U.K. fmg23@cam.ac.uk fr222@cam.ac.uk.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019858:Enteroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D052216:Glucagon-Like Peptide 1; D002118:Calcium