Abstract
A peptide corresponding to a proteinase-activated receptor 2 (PAR2)-activating peptide with an N-terminal furoyl group modification, 2-furoyl-LIGRLO-NH2, was assessed for PAR2-dependent and -independent biological activities. 2-Furoyl-LIGRLO-NH2 was equally effective to and 10 to 25 times more potent than SLIGRLNH2 for increasing intracellular calcium in cultured human and rat PAR2-expressing cells, respectively. In bioassays of tissue PAR2 activity, measured as arterial vasodilation and hyperpolarization, 2-furoyl-LIGRLO-NH2 was 10 to 300 times more potent than SLIGRL-NH2. Unlike trans-cinnamoyl-LIGRLO-NH2, 2-furoyl-LI-GRLO-NH2 did not cause a prominent non-PAR2-mediated contraction of murine femoral arteries. In conclusion, 2-furoyl-LI-GRLO-NH2 represents the most potent and selective activator of PAR2 in biological systems described to date.
Footnotes
-
These studies were supported by grants from the Canadian Institutes of Health Research (CIHR) (C.R.T., M.D.H.), the Heart and Stroke Foundation of Alberta, Northwest Territories and Nunavut (C.R.T., M.D.H.), the Johnson and Johnson Focused Giving Program (M.D.H.), and a CIHR-Servier Canada/International University Industry Partnership (M.D.H.). J.J.M. was supported by a postdoctoral fellowship from the Heart and Stroke Foundation of Canada in conjunction with CIHR and AstraZeneca. Measurements of intracellular calcium were made possible by an equipment grant from the Alberta Heritage Foundation for Medical Research.
-
DOI: 10.1124/jpet.103.064584.
-
ABBREVIATIONS: PAR, proteinase-activated receptor; KNRK, Kirsten virus-transformed rat kidney; HEK, human embryonic kidney.
- Received December 17, 2003.
- Accepted February 19, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|