<figure><img src="image_53.png" /></figure>

Journal of Pharmacology, 175, 407-411. https://doi.org/10.1111/bph.14112

Bohm, S. K., Kong, W., Bromme, D., Smeekens, S. P., Anderson, D. C., Connolly, A., Kahn, M., Nelken, N. A., Coughlin, S. R., Payan, D. G., & Bunnett, N. W. (1996). Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. *The Biochemical Journal*, *314*(Pt 3), 1009-1016. https://doi.org/10.1042/bj3141009

Borgstrom, B., Dahlqvist, A., Lundh, G., & Sjovall, J. (1957). Studies of intestinal digestion and absorption in the human. *The Journal of Clinical Investigation*, *36*, 1521-1536. https://doi.org/10.1172/JCI103549

Buresi, M. C., Schleihauf, E., Vergnolle, N., Buret, A., Wallace, J. L., Hollenberg, M. D., & MacNaughton, W. K. (2001). Protease-activated receptor-1 stimulates Ca²⁺-dependent Cl⁻ secretion in human intestinal epithelial cells. *American Journal of Physiology. Gastrointestinal and Liver Physiology*, *281*, G323-G332. https://doi.org/10.1152/ajpgi.2001.281.2.G323

Caminero, A., McCarville, J. L., Galipeau, H. J., Deraison, C., Bernier, S. P., Constante, M., Rolland, C., Meisel, M., Murray, J. A., Yu, X. B., Alaedini, A., Coombes, B. K., Bercik, P., Southward, C. M., Ruf, W., Jabri, B., Chirdo, F. G., Casqueiro, J., Surette, M. G., ... Verdu, E. F. (2019). Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. *Nature Communications*, *10*, 1198. https://doi.org/10.1038/s41467-019-09037-9

Canivet, C., Gourgou-Bourgade, S., Napoleon, B., Palazzo, L., Flori, N., Guibert, P., Piessen, G., Farges-Bancel, D., Seitz, J. F., Assenat, E., Vendrely, V., Truant, S., Vanbiervliet, G., Berthelemy, P., Garcia, S., Gomez-Brouchet, A., Buscail, L., Bournet, B., & Bacap Consortium. (2018). A prospective clinical and biological database for pancreatic adenocarcinoma: The BACAP cohort. *BMC Cancer*, *18*, 986. https://doi.org/10.1186/s12885-018-4906-4

Cenac, N., Coelho, A. M., Nguyen, C., Compton, S., Andrade-Gordon, P., MacNaughton, W. K., Wallace, J. L., Hollenberg, M. D., Bunnett, N. W., Garcia-Villar, R., Bueno, L., & Vergnolle, N. (2002). Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. *The American Journal of Pathology*, *161*, 1903-1915. https://doi.org/10.1016/S0002-9440(10)64466-5

Chin, A. C., Vergnolle, N., MacNaughton, W. K., Wallace, J. L., Hollenberg, M. D., & Buret, A. G. (2003). Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability. *Proceedings of the National Academy of Sciences of the United States of America*, *100*, 11104-11109. https://doi.org/10.1073/pnas.1831452100

Cuffe, J. E., Bertog, M., Velazquez-Rocha, S., Dery, O., Bunnett, N., & Korbmacher, C. (2002). Basolateral PAR-2 receptors mediate KCl secretion and inhibition of Na⁺ absorption in the mouse distal colon. *The Journal of Physiology*, *539*, 209-222. https://doi.org/10.1113/jphysiol.2001.013159

Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. *British Journal of Pharmacology*, *179*(15), 3907-3913. https://doi.org/10.1111/bph.15868

D'Andrea, M. R., Derian, C. K., Leturcq, D., Baker, S. M., Brunmark, A., Ling, P., Darrow, A. L., Santulli, R. J., Brass, L. F., & Andrade-Gordon, P. (1998). Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. *The Journal of Histochemistry and Cytochemistry*, *46*, 157-164. https://doi.org/10.1177/002215549804600204

Darmoul, D., Gratio, V., Devaud, H., Lehy, T., & Laburthe, M. (2003). Aberrant expression and activation of the thrombin receptor protease-activated receptor-1 induces cell proliferation and motility in human

colon cancer cells. *The American Journal of Pathology*, *162*, 1503-1513. https://doi.org/10.1016/S0002-9440(10)64283-6

Darmoul, D., Gratio, V., Devaud, H., Peiretti, F., & Laburthe, M. (2004). Activation of proteinase-activated receptor 1 promotes human colon cancer cell proliferation through epidermal growth factor receptor transactivation. *Molecular Cancer Research*, *2*, 514-522. https://doi.org/10.1158/1541-7786.514.2.9

De Bruyn, M., Ceuleers, H., Hanning, N., Berg, M., De Man, J. G., Hulpiau, P., Hermans, C., Stenman, U. H., Koistinen, H., Lambeir, A. M., De Winter, B. Y., & De Meester, I. (2021). Proteolytic cleavage of bioactive peptides and protease-activated receptors in acute and postcolitis. *International Journal of Molecular Sciences*, *22*, 10711. https://doi.org/10.3390/ijms221910711

Dulon, S., Cande, C., Bunnett, N. W., Hollenberg, M. D., Chignard, M., & Pidard, D. (2003). Proteinase-activated receptor-2 and human lung epithelial cells: Disarming by neutrophil serine proteinases. *American Journal of Respiratory Cell and Molecular Biology*, *28*, 339-346. https://doi.org/10.1165/rcmb.4908

Goldberg, D. M., Campbell, R., & Roy, A. D. (1968). Binding of trypsin and chymotrypsin by human intestinal mucosa. *Biochimica et Biophysica Acta*, *167*, 613-615. https://doi.org/10.1016/0005-2744(68)90053-3

Goldberg, D. M., Campbell, R., & Roy, A. D. (1969). Fate of trypsin and chymotrypsin in the human small intestine. *Gut*, *10*, 477-483.

Hollenberg, M. D., Mihara, K., Polley, D., Suen, J. Y., Han, A., Fairlie, D. P., & Ramachandran, R. (2014). Biased signalling and proteinase-activated receptors (PARs): Targeting inflammatory disease. *British Journal of Pharmacology*, *171*, 1180-1194. https://doi.org/10.1111/bph.12544

Holzhausen, M., Spolidorio, L. C., Ellen, R. P., Jobin, M. C., Steinhoff, M., Andrade-Gordon, P., & Vergnolle, N. (2006). Protease-activated receptor-2 activation: A major role in the pathogenesis of Porphyromonas gingivalis infection. *The American Journal of Pathology*, *168*, 1189-1199. https://doi.org/10.2353/ajpath.2006.050658

lablokov, V., Hirota, C. L., Peplowski, M. A., Ramachandran, R., Mihara, K., Hollenberg, M. D., & MacNaughton, W. K. (2014). Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. *The Journal of Biological Chemistry*, *289*, 34366-34377. https://doi.org/10.1074/jbc.M114.610485

Kaiserman, D., Zhao, P., Rowe, C. L., Leong, A., Barlow, N., Joeckel, L. T., Hitchen, C., Stewart, S. E., Hollenberg, M. D., Bunnett, N., Suhrbier, A., & Bird, P. I. (2022). Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2. *PLoS ONE*, *17*, e0270584. https://doi.org/10.1371/journal.pone.0270584

Kawabata, A., Saifeddine, M., Al-Ani, B., Leblond, L., & Hollenberg, M. D. (1999). Evaluation of proteinase-activated receptor-1 (PAR1) agonists and antagonists using a cultured cell receptor desensitization assay: Activation of PAR2 by PAR1-targeted ligands. *The Journal of Pharmacology and Experimental Therapeutics*, *288*, 358-370.

Kong, W., McConalogue, K., Khitin, L. M., Hollenberg, M. D., Payan, D. G., Bohm, S. K., & Bunnett, N. W. (1997). Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. *Proceedings of the National Academy of Sciences of the United States of America*, *94*, 8884-8889. https://doi.org/10.1073/pnas.94.16.8884

Lau, C., Lytle, C., Straus, D. S., & DeFea, K. A. (2011). Apical and basolateral pools of proteinase-activated receptor-2 direct distinct signaling events in the intestinal epithelium. *American Journal of Physiology. Cell Physiology*, *300*, C113-C123. https://doi.org/10.1152/ajpcell.00162.2010

Lilley, E., Stanford, S. C., Kendall, D. E., Alexander, S. P. H., Cirino, G., Docherty, J. R., George, C. H., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Sobey, C. G., Stefanska, B., Stephens, G., Teixeira, M., & Ahluwalia, A. (2020). ARRIVE 2.0 and the British Journal of Pharmacology: Updated guidance for 2020. *British Journal of Pharmacology*, *177*, 3611-3616. https://doi.org/10.1111/bph.15178
<figure><img src="image_55.png" /></figure>

Journal of Pharmacology, 175, 407-411. https://doi.org/10.1111/bph.14112

Bohm, S. K., Kong, W., Bromme, D., Smeekens, S. P., Anderson, D. C.,
Connolly, A., Kahn, M., Nelken, N. A., Coughlin, S. R., Payan, D. G., &
Bunnett, N. W. (1996). Molecular cloning, expression and potential
functions of the human proteinase-activated receptor-2. *The Biochemi-
cal Journal*, *314*(Pt 3), 1009-1016. https://doi.org/10.1042/
bj3141009

Borgstrom, B., Dahlqvist, A., Lundh, G., & Sjovall, J. (1957). Studies of intestinal digestion and absorption in the human. *The Journal of Clinical Investigation*, **36**, 1521-1536. https://doi.org/10.1172/JCI103549

Buresi, M. C., Schleihauf, E., Vergnolle, N., Buret, A., Wallace, J. L., Hollenberg, M. D., & MacNaughton, W. K. (2001). Protease-activated receptor-1 stimulates Ca²⁺-dependent Cl⁻ secretion in human intestinal epithelial cells. *American Journal of Physiology. Gastrointestinal and Liver Physiology*, **281**, G323-G332. https://doi.org/10.1152/ajpgi.2001.281.2.G323

Caminero, A., McCarville, J. L., Galipeau, H. J., Deraison, C., Bernier, S. P., Constante, M., Rolland, C., Meisel, M., Murray, J. A., Yu, X. B., Alaedini, A., Coombes, B. K., Bercik, P., Southward, C. M., Ruf, W., Jabri, B., Chirdo, F. G., Casqueiro, J., Surette, M. G., ... Verdu, E. F. (2019). Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. *Nature Communications*, **10**, 1198. https://doi.org/10.1038/s41467-019-09037-9

Canivet, C., Gourgou-Bourgade, S., Napoleon, B., Palazzo, L., Flori, N., Guibert, P., Piessen, G., Farges-Bancel, D., Seitz, J. F., Assenat, E., Vendrely, V., Truant, S., Vanbiervliet, G., Berthelemy, P., Garcia, S., Gomez-Brouchet, A., Buscail, L., Bournet, B., & Bacap Consortium. (2018). A prospective clinical and biological database for pancreatic adenocarcinoma: The BACAP cohort. *BMC Cancer*, **18**, 986. https://doi.org/10.1186/s12885-018-4906-4

Cenac, N., Coelho, A. M., Nguyen, C., Compton, S., Andrade-Gordon, P., MacNaughton, W. K., Wallace, J. L., Hollenberg, M. D., Bunnett, N. W., Garcia-Villar, R., Bueno, L., & Vergnolle, N. (2002). Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. *The American Journal of Pathology*, **161**, 1903-1915. https://doi.org/10.1016/S0002-9440(10)64466-5

Chin, A. C., Vergnolle, N., MacNaughton, W. K., Wallace, J. L., Hollenberg, M. D., & Buret, A. G. (2003). Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability. *Proceedings of the National Academy of Sciences of the United States of America*, **100**, 11104-11109. https://doi.org/10.1073/pnas.1831452100

Cuffe, J. E., Bertog, M., Velazquez-Rocha, S., Dery, O., Bunnett, N., & Korbmacher, C. (2002). Basolateral PAR-2 receptors mediate KCl secretion and inhibition of Na⁺ absorption in the mouse distal colon. *The Journal of Physiology*, **539**, 209-222. https://doi.org/10.1113/jphysiol.2001.013159

Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. *British Journal of Pharmacology*, **179**(15), 3907-3913. https://doi.org/10.1111/bph.15868

D'Andrea, M. R., Derian, C. K., Leturcq, D., Baker, S. M., Brunmark, A., Ling, P., Darrow, A. L., Santulli, R. J., Brass, L. F., & Andrade-Gordon, P. (1998). Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. *The Journal of Histochemistry and Cytochemistry*, **46**, 157-164. https://doi.org/10.1177/002215549804600204

Darmoul, D., Gratio, V., Devaud, H., Lehy, T., & Laburthe, M. (2003). Aber-
rant expression and activation of the thrombin receptor protease-
activated receptor-1 induces cell proliferation and motility in human

colon cancer cells. *The American Journal of Pathology*, **162**, 1503-1513.
https://doi.org/10.1016/S0002-9440(10)64283-6

Darmoul, D., Gratio, V., Devaud, H., Peiretti, F., & Laburthe, M. (2004). Activation of proteinase-activated receptor 1 promotes human colon cancer cell proliferation through epidermal growth factor receptor transactivation. *Molecular Cancer Research*, **2**, 514-522. https://doi.org/10.1158/1541-7786.514.2.9

De Bruyn, M., Ceuleers, H., Hanning, N., Berg, M., De Man, J. G., Hulpiau, P., Hermans, C., Stenman, U. H., Koistinen, H., Lambeir, A. M., De Winter, B. Y., & De Meester, I. (2021). Proteolytic cleavage of bio-active peptides and protease-activated receptors in acute and post-colitis. *International Journal of Molecular Sciences*, **22**, 10711. https://doi.org/10.3390/ijms221910711

Dulon, S., Cande, C., Bunnett, N. W., Hollenberg, M. D., Chignard, M., & Pidard, D. (2003). Proteinase-activated receptor-2 and human lung epithelial cells: Disarming by neutrophil serine proteinases. *American Journal of Respiratory Cell and Molecular Biology*, **28**, 339-346. https://doi.org/10.1165/rcmb.4908

Goldberg, D. M., Campbell, R., & Roy, A. D. (1968). Binding of trypsin and chymotrypsin by human intestinal mucosa. *Biochimica et Biophysica Acta*, **167**, 613-615. https://doi.org/10.1016/0005-2744(68)90053-3

Goldberg, D. M., Campbell, R., & Roy, A. D. (1969). Fate of trypsin and chymotrypsin in the human small intestine. *Gut*, **10**, 477-483.

Hollenberg, M. D., Mihara, K., Polley, D., Suen, J. Y., Han, A., Fairlie, D. P., & Ramachandran, R. (2014). Biased signalling and proteinase-activated receptors (PARs): Targeting inflammatory disease. *British Journal of Pharmacology*, **171**, 1180-1194. https://doi.org/10.1111/bph.12544

Holzhausen, M., Spolidorio, L. C., Ellen, R. P., Jobin, M. C., Steinhoff, M., Andrade-Gordon, P., & Vergnolle, N. (2006). Protease-activated receptor-2 activation: A major role in the pathogenesis of Porphyromonas gingivalis infection. *The American Journal of Pathology*, **168**, 1189-1199. https://doi.org/10.2353/ajpath.2006.050658

lablokov, V., Hirota, C. L., Peplowski, M. A., Ramachandran, R., Mihara, K., Hollenberg, M. D., & MacNaughton, W. K. (2014). Proteinase-activated receptor 2 (PAR2) decreases apoptosis in colonic epithelial cells. *The Journal of Biological Chemistry*, **289**, 34366-34377. https://doi.org/10.1074/jbc.M114.610485

Kaiserman, D., Zhao, P., Rowe, C. L., Leong, A., Barlow, N., Joeckel, L. T., Hitchen, C., Stewart, S. E., Hollenberg, M. D., Bunnett, N., Suhrbier, A., & Bird, P. I. (2022). Granzyme K initiates IL-6 and IL-8 release from epithelial cells by activating protease-activated receptor 2. *PLoS ONE*, **17**, e0270584. https://doi.org/10.1371/journal.pone.0270584

Kawabata, A., Saifeddine, M., Al-Ani, B., Leblond, L., & Hollenberg, M. D. (1999). Evaluation of proteinase-activated receptor-1 (PAR1) agonists and antagonists using a cultured cell receptor desensitization assay: Activation of PAR2 by PAR1-targeted ligands. *The Journal of Pharmacology and Experimental Therapeutics*, **288**, 358-370.

Kong, W., McConalogue, K., Khitin, L. M., Hollenberg, M. D., Payan, D. G., Bohm, S. K., & Bunnett, N. W. (1997). Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. *Proceedings of the National Academy of Sciences of the United States of America*, **94**, 8884-8889. https://doi.org/10.1073/pnas.94.16.8884

Lau, C., Lytle, C., Straus, D. S., & DeFea, K. A. (2011). Apical and basolateral pools of proteinase-activated receptor-2 direct distinct signaling events in the intestinal epithelium. *American Journal of Physiology. Cell Physiology*, **300**, C113-C123. https://doi.org/10.1152/ajpcell.00162.2010

Lilley, E., Stanford, S. C., Kendall, D. E., Alexander, S. P. H., Cirino, G., Docherty, J. R., George, C. H., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Sobey, C. G., Stefanska, B., Stephens, G., Teixeira, M., & Ahluwalia, A. (2020). ARRIVE 2.0 and the British Journal of Pharmacology: Updated guidance for 2020. *British Journal of Pharmacology*, **177**, 3611-3616. https://doi.org/10.1111/bph.15178
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Ramachandran, R., Noorbakhsh, F., Defea, K., & Hollenberg, M. D. (2012). Targeting proteinase-activated receptors: Therapeutic potential and challenges. *Nature Reviews. Drug Discovery*, *11*, 69–86. https://doi.org/10.1038/nrd3615

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Roka, R., Demaude, J., Cenac, N., Ferrier, L., Salvador-Cartier, C., Garcia-Villar, R., Fioramonti, J., & Bueno, L. (2007). Colonic luminal proteases
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Schechter, N. M., Brass, L. F., Lavker, R. M., & Jensen, P. J. (1998). Reaction of mast cell proteases tryptase and chymase with protease activated receptors (PARs) on keratinocytes and fibroblasts. *Journal of Cellular Physiology*, 176, 365-373. https://doi.org/10.1002/(SICI)1097-4652 (199808)176:2<365::AID-JCP15>3.0.CO;2-2

Sebert, M., Denadai-Souza, A., Quaranta, M., Racaud-Sultan, C., Chabot, S., Lluel, P., Monjotin, N., Alric, L., Portier, G., Kirzin, S., Bonnet, D., Ferrand, A., & Vergnolle, N. (2018). Thrombin modifies growth, proliferation and apoptosis of human colon organoids: A protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism. *British Journal of Pharmacology*, 175, 3656-3668. https://doi.org/10.1111/bph.14430

Sebert, M., Sola-Tapias, N., Mas, E., Barreau, F., & Ferrand, A. (2019). Protease-activated receptors in the intestine: Focus on inflammation and cancer. *Front Endocrinol (Lausanne)*, 10, 717. https://doi.org/10.3389/fendo.2019.00717

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Smith, J. S., Ediss, I., Mullinger, M. A., & Bogoch, A. (1971). Fecal chymotrypsin and trypsin determinations. *Canadian Medical Association Journal*, 104, 691-4 passim.

Stefansson, K., Brattsand, M., Roosterman, D., Kempkes, C., Bocheva, G., Steinhoff, M., & Egelrud, T. (2008). Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. *The Journal of Investigative Dermatology*, 128, 18-25. https://doi.org/10.1038/sj.jid.5700965

Swystun, V. A., Renaux, B., Moreau, F., Wen, S., Peplowski, M. A., Hollenberg, M. D., & MacNaughton, W. K. (2009). Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase Cζ. *American Journal of Physiology. Gastrointestinal and Liver Physiology*, 297, G60-G70. https://doi.org/10.1152/ajpgi.00096.2009

Tam, S. W., Fenton, J. W. 2nd, & Detwiler, T. C. (1980). Platelet thrombin receptors. Binding of alpha-thrombin is coupled to signal generation by a chymotrypsin-sensitive mechanism. *The Journal of Biological Chemistry*, 255, 6626-6632. https://doi.org/10.1016/S0021-9258 (18)43615-0

Tanaka, Y., Sekiguchi, F., Hong, H., & Kawabata, A. (2008). PAR2 triggers IL-8 release via MEK/ERK and PI3-kinase/Akt pathways in GI

epithelial cells. *Biochemical and Biophysical Research Communications*, 377, 622-626. https://doi.org/10.1016/j.bbrc.2008.10.018

Targos, B., Baranska, J., & Pomorski, P. (2005). Store-operated calcium entry in physiology and pathology of mammalian cells. *Acta Biochimica Polonica*, 52, 397-409. https://doi.org/10.18388/abp.2005_3452

van der Merwe, J. Q., Hollenberg, M. D., & MacNaughton, W. K. (2008). EGF receptor transactivation and MAP kinase-mediated proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells. *American Journal of Physiology. Gastrointestinal and Liver Physiology*, 294, G441-G451. https://doi.org/10.1152/ajpgi.00303.2007

Vergnolle, N. (2005). Clinical relevance of proteinase activated receptors (pars) in the gut. *Gut*, 54, 867-874. https://doi.org/10.1136/gut.2004.048876

Vergnolle, N. (2016). Protease inhibition as new therapeutic strategy for GI diseases. *Gut*, 65, 1215-1224. https://doi.org/10.1136/gutjnl-2015-309147

Wang, H., Ubl, J. J., Stricker, R., & Reiser, G. (2002). Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. *American Journal of Physiology. Cell Physiology*, 283, C1351-C1364. https://doi.org/10.1152/ajpcell.00001.2002

Zhang, X., Xin, P., Yoast, R. E., Emrich, S. M., Johnson, M. T., Pathak, T., Benson, J. C., Azimi, I., Gill, D. L., Monteith, G. R., & Trebak, M. (2020). Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels. *Cell Calcium*, 91, 102281. https://doi.org/10.1016/j.ceca.2020.102281

## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Guignard, S., Saifeddine, M., Mihara, K., Motahhary, M., Savignac, M., Guiraud, L., Sagnat, D., Sebbag, M., Khou, S., Rolland, C., Edir, A., Bournet, B., Buscail, L., Buscail, E., Alric, L., Camare, C., Ambli, M., Vergnolle, N., Hollenberg, M. D., ... Bonnart, C. (2024). Chymotrypsin activity signals to intestinal epithelium by protease-activated receptor-dependent mechanisms. *British Journal of Pharmacology*, 1-25. https://doi.org/10.1111/bph.16341
<figure><img src="image_57.png" /></figure>

activate colonocyte proteinase-activated receptor-2 and regulate paracellular permeability in mice. *Neurogastroenterology and Motility*, 19, 57-65. https://doi.org/10.1111/j.1365-2982.2006.00851.x

Schechter, N. M., Brass, L. F., Lavker, R. M., & Jensen, P. J. (1998). Reaction of mast cell proteases tryptase and chymase with protease activated receptors (PARs) on keratinocytes and fibroblasts. *Journal of Cellular Physiology*, 176, 365-373. https://doi.org/10.1002/(SICI)1097-4652 (199808)176:2<365::AID-JCP15>3.0.CO;2-2

Sebert, M., Denadai-Souza, A., Quaranta, M., Racaud-Sultan, C., Chabot, S., Lluel, P., Monjotin, N., Alric, L., Portier, G., Kirzin, S., Bonnet, D., Ferrand, A., & Vergnolle, N. (2018). Thrombin modifies growth, proliferation and apoptosis of human colon organoids: A protease-activated receptor 1- and protease-activated receptor 4-dependent mechanism. *British Journal of Pharmacology*, 175, 3656-3668. https://doi.org/10.1111/bph.14430

Sebert, M., Sola-Tapias, N., Mas, E., Barreau, F., & Ferrand, A. (2019). Protease-activated receptors in the intestine: Focus on inflammation and cancer. *Front Endocrinol (Lausanne)*, 10, 717. https://doi.org/10.3389/fendo.2019.00717

Singer, M. V., & Niebergall-Roth, E. (2009). Secretion from acinar cells of the exocrine pancreas: Role of enteropancreatic reflexes and cholecystokinin. *Cell Biology International*, 33, 1-9. https://doi.org/10.1016/j.cellbi.2008.09.008

Smith, J. S., Ediss, I., Mullinger, M. A., & Bogoch, A. (1971). Fecal chymotrypsin and trypsin determinations. *Canadian Medical Association Journal*, 104, 691-4 passim.

Stefansson, K., Brattsand, M., Roosterman, D., Kempkes, C., Bocheva, G., Steinhoff, M., & Egelrud, T. (2008). Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. *The Journal of Investigative Dermatology*, 128, 18-25. https://doi.org/10.1038/sj.jid.5700965

Swystun, V. A., Renaux, B., Moreau, F., Wen, S., Peplowski, M. A., Hollenberg, M. D., & MacNaughton, W. K. (2009). Serine proteases decrease intestinal epithelial ion permeability by activation of protein kinase Cζ. *American Journal of Physiology. Gastrointestinal and Liver Physiology*, 297, G60-G70. https://doi.org/10.1152/ajpgi.00096.2009

Tam, S. W., Fenton, J. W. 2nd, & Detwiler, T. C. (1980). Platelet thrombin receptors. Binding of alpha-thrombin is coupled to signal generation by a chymotrypsin-sensitive mechanism. *The Journal of Biological Chemistry*, 255, 6626-6632. https://doi.org/10.1016/S0021-9258 (18)43615-0

Tanaka, Y., Sekiguchi, F., Hong, H., & Kawabata, A. (2008). PAR2 triggers IL-8 release via MEK/ERK and PI3-kinase/Akt pathways in GI

epithelial cells. *Biochemical and Biophysical Research Communications*, 377, 622-626. https://doi.org/10.1016/j.bbrc.2008.10.018

Targos, B., Baranska, J., & Pomorski, P. (2005). Store-operated calcium entry in physiology and pathology of mammalian cells. *Acta Biochimica Polonica*, 52, 397-409. https://doi.org/10.18388/abp.2005.3452

van der Merwe, J. Q., Hollenberg, M. D., & MacNaughton, W. K. (2008). EGF receptor transactivation and MAP kinase-mediated proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells. *American Journal of Physiology. Gastrointestinal and Liver Physiology*, 294, G441-G451. https://doi.org/10.1152/ajpgi.00303.2007

Vergnolle, N. (2005). Clinical relevance of proteinase activated receptors (pars) in the gut. *Gut*, 54, 867-874. https://doi.org/10.1136/gut.2004.048876

Vergnolle, N. (2016). Protease inhibition as new therapeutic strategy for GI diseases. *Gut*, 65, 1215-1224. https://doi.org/10.1136/gutjnl-2015-309147

Wang, H., Ubl, J. J., Stricker, R., & Reiser, G. (2002). Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. *American Journal of Physiology. Cell Physiology*, 283, C1351-C1364. https://doi.org/10.1152/ajpcell.00001.2002

Zhang, X., Xin, P., Yoast, R. E., Emrich, S. M., Johnson, M. T., Pathak, T., Benson, J. C., Azimi, I., Gill, D. L., Monteith, G. R., & Trebak, M. (2020). Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels. *Cell Calcium*, 91, 102281. https://doi.org/10.1016/j.ceca.2020.102281

## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Guignard, S., Saifeddine, M., Mihara, K., Motahhary, M., Savignac, M., Guiraud, L., Sagnat, D., Sebbag, M., Khou, S., Rolland, C., Edir, A., Bournet, B., Buscail, L., Buscail, E., Alric, L., Camare, C., Ambli, M., Vergnolle, N., Hollenberg, M. D., ... Bonnart, C. (2024). Chymotrypsin activity signals to intestinal epithelium by protease-activated receptor-dependent mechanisms. *British Journal of Pharmacology*, 1-25. https://doi.org/10.1111/bph.16341