title: Transient receptor potential ankyrin 1 (TRPA1) channel activation by the thienopyridine-type drugs ticlopidine, clopidogrel, and prasugrel.
abstract: Transient receptor potential A1 (TRPA1) is widely expressed throughout the human and animal organism, including the dorsal root ganglia as well as the bladder, stomach and small intestine. Here, we examined the effect of three platelet aggregation inhibitors on TRPA1: ticlopidine, clopidogrel and prasugrel. Utilising fluorometric Ca(2+) influx analysis and electrophysiological whole cell measurements in TRPA1-expressing HEK293 and in human enterochromaffin-like QGP-1 cells, we found that ticlopidine, clopidogrel and prasugrel are direct activators of TRPA1. Although this polymodal channel commonly contributes to the perception of pain, temperature and chemical irritants, recent studies provide evidence for its involvement in the release of serotonin (5-HT) from enterochromaffin cells. Therefore, we further investigated the ability of ticlopidine, clopidogrel and prasugrel to stimulate 5-HT release from QGP-1 cells. We could determine 5-HT in supernatants from cultured QGP-1 cells upon treatment with ticlopidine and clopidogrel but not with prasugrel. These findings indicate that a robust TRPA1 activation by ticlopidine and clopidogrel correlates with the stimulatory effect on the secretion of 5-HT. As recipients of ticlopidine and clopidogrel frequently complain about gastrointestinal adverse events such as nausea, vomiting and diarrhoea, an activation of TRPA1 may contribute to adverse effects of such drugs in the digestive system.
authors.affiliation: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Hartung
authors.affiliation: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, University of Leipzig, Leipzig, Germany. Electronic address: kerstin.hill@medizin.uni-leipzig.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hill
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000077144:Clopidogrel; D019861:Enterochromaffin-like Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012701:Serotonin / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D059008:Time-Lapse Imaging; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D013876:Thiophenes; D050051:Transient Receptor Potential Channels; C446540:thienopyridine; D012701:Serotonin; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine; D002118:Calcium
keywords: Clopidogrel; Prasugrel; QGP-1; Serotonin; TRPA1; Thienopyridine; Ticlopidine