Protease‐Activated Receptor 2 Activation Provokes an Increase in Intracellular Calcium and Serotonin Secretion in a Human Enteroendocrine Cell Line

The P-STS human ileal enteroendocrine tumor cell line responds with an increase in intracellular calcium and serotonin secretion to acetylcholine and histamine. Here we show that the cells react similarly to the protease-activated receptor 2 (PAR2) agonists trypsin and SLIGRL-NH2 peptide. The calcium increase induced by both agonists is inhibited by the PAR2 antagonist I-191. PAR2-IN-1, another PAR2 antagonist, did not inhibit the response to the agonist peptide. Trypsin can also be looked upon as a surrogate for mast cell tryptase which cleaves PAR2 at the same site as trypsin. As mast cells may secrete tryptase simultaneously with histamine in close proximity to enteroendocrine cells, we tested whether trypsin and histamine might induce mutual desensitization. Histamine did not desensitize the response to trypsin and trypsin did not desensitize the response to histamine or acetylcholine. Further known effects of short-time incubation with trypsin, namely phosphorylation of p38 mitogen-activated protein kinase and activation of the nuclear factor κB pathway, were not detected in P-STS cells. In conclusion, our findings indicate that serotonin secretion by enterochromaffin cells in response to PAR2 activation might contribute to gastrointestinal symptoms after mast cell activation by food allergens or irritable bowel syndrome. Our data suggest that histamine and mast cell tryptase may have at least additive effects on serotonin secretion.