GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels to Stimulate GLP-1 Secretion
| Autor: | Oleg G. Chepurny, Colin A. Leech, George G. Holz, Michael W. Roe |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Agonist medicine.medical_specialty medicine.drug_class Biology Endoplasmic Reticulum Proglucagon Transfection Receptors G-Protein-Coupled 03 medical and health sciences Transient receptor potential channel 0302 clinical medicine Endocrinology Glucagon-Like Peptide 1 Isothiocyanates Internal medicine Cyclic AMP medicine Animals Humans Patch clamp Luciferases Receptor TRPA1 Cation Channel Molecular Biology Original Research HEK 293 cells General Medicine Glucagon Cyclic AMP-Dependent Protein Kinases Glucagon-like peptide-1 Recombinant Proteins Rats Cell biology HEK293 Cells Pyrimidines 030104 developmental biology Gene Expression Regulation Ethanolamines Monoterpenes Cymenes Calcium Mutant Proteins Ion Channel Gating 030217 neurology & neurosurgery Intestinal L Cells |
| Zdroj: | Molecular Endocrinology. 30:614-629 |
| ISSN: | 1944-9917 0888-8809 |
| Popis: | GPR119 is a G protein-coupled receptor expressed on intestinal L cells that synthesize and secrete the blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1). GPR119 agonists stimulate the release of GLP-1 from L cells, and for this reason there is interest in their potential use as a new treatment for type 2 diabetes mellitus. AS1269574 is one such GPR119 agonist, and it is the prototype of a series of 2,4,6 trisubstituted pyrimidines that exert positive glucoregulatory actions in mice. Here we report the unexpected finding that AS1269574 stimulates GLP-1 release from the STC-1 intestinal cell line by directly promoting Ca(2+) influx through transient receptor potential ankyrin 1 (TRPA1) cation channels. These GPR119-independent actions of AS1269574 are inhibited by TRPA1 channel blockers (AP-18, A967079, HC030031) and are not secondary to intracellular Ca(2+) release or cAMP production. Patch clamp studies reveal that AS1269574 activates an outwardly rectifying membrane current with properties expected of TRPA1 channels. However, the TRPA1 channel-mediated action of AS1269574 to increase intracellular free calcium concentration is not replicated by GPR119 agonists (AR231453, oleoylethanolamide) unrelated in structure to AS1269574. Using human embryonic kidney-293 cells expressing recombinant rat TRPA1 channels but not GPR119, direct TRPA1 channel activating properties of AS1269574 are validated. Because we find that AS1269574 also acts in a conventional GPR119-mediated manner to stimulate proglucagon gene promoter activity in the GLUTag intestinal L cell line, new findings reported here reveal the surprising capacity of AS1269574 to act as a dual agonist at two molecular targets (GPR119/TRPA1) important to the control of L-cell function and type 2 diabetes mellitus drug discovery research. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|