Mast Cell Tryptase Regulates Rat Colonic Myocytes Through Proteinase-activated Receptor 2

Overview

Journal J Clin Invest

Specialty General Medicine

Date 1997 Sep 18

PMID 9294103

Citations 91

Authors

C U Corvera

O Dery

K McConalogue

S K Bohm

L M Khitin

G H Caughey

D G Payan

N W Bunnett

Affiliations

Soon will be listed here.

Abstract

Proteinase-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin-like enzymes. PAR-2 is highly expressed by small intestinal enterocytes where it is activated by luminal trypsin. The location, mechanism of activation, and biological functions of PAR-2 in the colon, however, are unknown. We localized PAR-2 to the muscularis externa of the rat colon by immunofluorescence. Myocytes in primary culture also expressed PAR-2, assessed by immunofluorescence and RT-PCR. Trypsin, SLIGRL-NH2 (corresponding to the PAR-2 tethered ligand), mast cell tryptase, and a filtrate of degranulated mast cells stimulated a prompt increase in [Ca2+]i in myocytes. The response to tryptase and the mast cell filtrate was inhibited by the tryptase inhibitor BABIM, and abolished by desensitization of PAR-2 with trypsin. PAR-2 activation inhibited the amplitude of rhythmic contractions of strips of rat colon. This response was unaffected by indomethacin, l-NG-nitroarginine methyl ester, a bradykinin B2 receptor antagonist and tetrodotoxin. Thus, PAR-2 is highly expressed by colonic myocytes where it may be cleaved and activated by mast cell tryptase. This may contribute to motility disturbances of the colon during conditions associated with mast cell degranulation.

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References

Blackhart B, Emilsson K, Nguyen D, Teng W, Martelli A, Nystedt S . Ligand cross-reactivity within the protease-activated receptor family. J Biol Chem. 1996; 271(28):16466-71. DOI: 10.1074/jbc.271.28.16466. View

Hwa J, Ghibaudi L, Williams P, Chintala M, Zhang R, Chatterjee M . Evidence for the presence of a proteinase-activated receptor distinct from the thrombin receptor in vascular endothelial cells. Circ Res. 1996; 78(4):581-8. DOI: 10.1161/01.res.78.4.581. View

Saifeddine M, Cheng C, Wang L, Hollenberg M . Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activity of receptor-derived peptides in gastric and vascular tissue. Br J Pharmacol. 1996; 118(3):521-30. PMC: 1909734. DOI: 10.1111/j.1476-5381.1996.tb15433.x. View

Grady E, Baluk P, Bohm S, Gamp P, Wong H, Payan D . Characterization of antisera specific to NK1, NK2, and NK3 neurokinin receptors and their utilization to localize receptors in the rat gastrointestinal tract. J Neurosci. 1996; 16(21):6975-86. PMC: 6579255. View

Molino M, Barnathan E, Numerof R, Clark J, Dreyer M, Cumashi A . Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem. 1997; 272(7):4043-9. DOI: 10.1074/jbc.272.7.4043. View

Ishihara H, Connolly A, Zeng D, Kahn M, Zheng Y, Timmons C . Protease-activated receptor 3 is a second thrombin receptor in humans. Nature. 1997; 386(6624):502-6. DOI: 10.1038/386502a0. View

Kong W, McConalogue K, Khitin L, Hollenberg M, Payan D, Bohm S . Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc Natl Acad Sci U S A. 1997; 94(16):8884-9. PMC: 23180. DOI: 10.1073/pnas.94.16.8884. View

Collins S, Gardner J . Cholecystokinin-induced contraction of dispersed smooth muscle cells. Am J Physiol. 1982; 243(6):G497-504. DOI: 10.1152/ajpgi.1982.243.6.G497. View

Tanaka T, McRae B, Cho K, Cook R, Fraki J, Johnson D . Mammalian tissue trypsin-like enzymes. Comparative reactivities of human skin tryptase, human lung tryptase, and bovine trypsin with peptide 4-nitroanilide and thioester substrates. J Biol Chem. 1983; 258(22):13552-7. View

10.

Caughey G, Viro N, Ramachandran J, Lazarus S, Borson D, Nadel J . Dog mastocytoma tryptase: affinity purification, characterization, and amino-terminal sequence. Arch Biochem Biophys. 1987; 258(2):555-63. DOI: 10.1016/0003-9861(87)90377-8. View

11.

Schwartz L, Yunginger J, Miller J, Bokhari R, Dull D . Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest. 1989; 83(5):1551-5. PMC: 303860. DOI: 10.1172/JCI114051. View

12.

Livingston E, PASSARO Jr E . Postoperative ileus. Dig Dis Sci. 1990; 35(1):121-32. DOI: 10.1007/BF01537233. View

13.

Vu T, Hung D, Wheaton V, Coughlin S . Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell. 1991; 64(6):1057-68. DOI: 10.1016/0092-8674(91)90261-v. View

14.

Ruoss S, Hartmann T, Caughey G . Mast cell tryptase is a mitogen for cultured fibroblasts. J Clin Invest. 1991; 88(2):493-9. PMC: 295370. DOI: 10.1172/JCI115330. View

15.

Shuttleworth C, Murphy R, Furness J . Evidence that nitric oxide participates in non-adrenergic inhibitory transmission to intestinal muscle in the guinea-pig. Neurosci Lett. 1991; 130(1):77-80. DOI: 10.1016/0304-3940(91)90231-h. View

16.

Goldstein S, Leong J, Schwartz L, Cooke D . Protease composition of exocytosed human skin mast cell protease-proteoglycan complexes. Tryptase resides in a complex distinct from chymase and carboxypeptidase. J Immunol. 1992; 148(8):2475-82. View

17.

Knudsen M, Svane D, Tottrup A . Action profiles of nitric oxide, S-nitroso-L-cysteine, SNP, and NANC responses in opossum lower esophageal sphincter. Am J Physiol. 1992; 262(5 Pt 1):G840-6. DOI: 10.1152/ajpgi.1992.262.5.G840. View

18.

Hartmann T, Ruoss S, Raymond W, Seuwen K, Caughey G . Human tryptase as a potent, cell-specific mitogen: role of signaling pathways in synergistic responses. Am J Physiol. 1992; 262(5 Pt 1):L528-34. DOI: 10.1152/ajplung.1992.262.5.L528. View

19.

Rhaleb N, Rouissi N, Jukic D, Regoli D, Henke S, Breipohl G . Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Qic8]bradykinin). Eur J Pharmacol. 1992; 210(2):115-20. DOI: 10.1016/0014-2999(92)90661-m. View

20.

Mari B, Guerin S, Far D, Breitmayer J, Belhacene N, Peyron J . Thrombin and trypsin-induced Ca(2+) mobilization in human T cell lines through interaction with different protease-activated receptors. FASEB J. 1996; 10(2):309-16. DOI: 10.1096/fasebj.10.2.8641564. View