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Distinct Activity of Peptide Mimetic Intracellular Ligands (Pepducins) for Proteinase‐Activated Receptor‐1 in Multiple Cells/Tissues
Author(s) -
KUBO SATOKO,
ISHIKI TSUYOSHI,
DOE ICHIKO,
SEKIGUCHI FUMIKO,
NISHIKAWA HIROYUKI,
KAWAI KENZO,
MATSUI HIROFUMI,
KAWABATA ATSUFUMI
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1378.087
Subject(s) - receptor , microbiology and biotechnology , chemistry , g protein coupled receptor , intracellular , aorta , amide , transfection , medicine , biology , endocrinology , biochemistry , gene
Proteinase‐activated receptor‐1 (PAR1), a G protein–coupled receptor (GPCR) for thrombin, can be activated not only by PAR1‐activating peptides (PAR1APs) based on the N‐terminal cryptic tethered ligand sequence but also by an N‐palmitoylated (Pal) peptide, Pal‐RCLSSSAVANRSKKSRALF‐amide (P1pal‐19), based on the intracellular loop 3 of PAR1, designated pepducin, in human platelets or PAR1‐transfected cells. The present article evaluated the actions of P1pal‐19 and also the shorter peptide, Pal‐RCLSSSAVANRS‐amide (P1pal‐12), known as a possible PAR1 antagonist, in multiple cells/tissues that naturally express PAR1. P1pal‐19 as well as a PAR1AP, TFLLR‐amide, evoked cytosolic Ca 2+ mobilization in cultured human lung epithelial cells (A549) and rat gastric mucosal epithelial cells (RGM1). P1pal‐19 and TFLLR‐amide, but not a PAR2‐activating peptide, SLIGRL‐amide, caused delayed prostaglandin E 2 formation in RGM1 cells. P1pal‐19, like TFLLR‐amide, produced endothelial NO‐dependent relaxation in rat aorta and epithelial prostanoid‐dependent relaxation in mouse bronchus. The P1pal‐19‐induced relaxation remained constant even after desensitization of PAR1 with TFLLR‐amide in either tissue. P1pal‐19 failed to mimic the contractile effects of TFLLR‐amide in the endothelium‐denuded preparations of rat aorta or superior mesenteric artery and the rat gastric longitudinal smooth muscle strips. P1pal‐12 partially inhibited the vasorelaxation caused by TFLLR‐amide and P1pal‐19, but not SLIGRL‐amide, in the rat aorta. Our data thus indicate that P1pal‐19 is capable of mimicking the effects of PAR1APs in the endothelial and epithelial, but not smooth muscle, cells/tissues, and suggest that P1pal‐12 may act as a PAR1 antagonist in the vascular endothelium.