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Vol. 290, Issue 2, 753-760, August 1999
Endocrine Research Group (B.A.-A., M.S., A.K., B.R., S.M., M.D.H.)
and Departments of Pharmacology and Therapeutics (M.D.H) and of
Medicine (M.D.H.), The University of Calgary, Faculty of Medicine,
Calgary, Alberta, Canada
A cloned rat proteinase-activated receptor
(PAR)2-expressing cell line (KNRK-rPAR2) was
used to study the structure-activity relationships (elevated
intracellular Ca2+) for a series of: 1)
PAR1-derived receptor-activating ligands (PAR1-APs) [SFLLR (P5), SFLLR-NH2
(P5-NH2), SFLLRNP (P7), SFLLRNP-NH2 (P7-NH2), and TFLLR-NH2 (TF-NH2)]
and 2) PAR2-derived-activating-peptides (PAR2-APs) [SLIGRL-NH2 (SL-NH2),
SLIGR-NH2 (GR-NH2), and SLIGKV-NH2 (KV-NH2)]. The activities of the PAR-APs were compared
with the PAR2-AP analog
trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-Orn-NH2
tc-NH2), which as a [3H]propionyl
derivative ([3H]propionyl-tc-NH2) was used to
develop a radioligand-binding assay for PAR2. The relative
potencies of the PAR-APs in the Ca2+-signaling assay were
tc-NH2 = SL-NH2 > KV-NH2
P5-NH2 > GR-NH2 > P7-NH2 > P7 > P5 > TF-NH2.
The reverse sequence PAR-APs, LSIGRL-NH2 (LS-NH2), LRGILS-NH2 (LR-NH2),
FSLLRY-NH2 (FSY-NH2), and FSLLR-NH2 (FS-NH2), as well as the Xenopus
PAR1-AP TFRIFD-NH2, were inactive. The relative
biological potencies of the peptides were in accord with their ability
to compete for the binding of
[3H]propionyl-tc-NH2 (tc-NH2 = SL-NH2 > GR-NH2 P5-NH2 > P5) to KNRK-rPAR2 cells, whereas
inactive peptides (FS-NH2; LR-NH2) showed no
appreciable binding competition. Our data therefore validate a
ligand-binding assay for the use in studies of PAR2 and
indicate that the relative biological potencies of the
PAR1-APs for activating rat PAR2 parallel their
ability to activate human PAR1. The relative receptor-binding activities of the PAR-APs, although in general agreement with their relative biological activities, point to differences in the intrinsic receptor-activating activities between the
several PAR-APs. The binding assay we have developed should prove of
use for the further study of PAR2-ligand interactions.
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