Protease-activated receptor-2 (PAR-2) is present in the rat hippocampus and is associated with neurodegeneration.
Protease-activated receptor-2 (PAR-2) is a seven-transmembrane G protein-coupled receptor that possesses a structure and activation mechanism similar to those of the thrombin receptor. It is activated by low concentrations of trypsin (300 pM) and a synthetic hexapeptide [sequence of serine, leucine, isoleucine, glycine, arginine, leucine (SLIGRL), the rodent PAR-2 "tethered ligand"] representing the first six amino acids following the putative PAR-2 cleavage site. Previous studies have indicated that alpha-thrombin and SFLLRN (synthetic hexapeptide sequence of serine, phenylalanine, leucine, leucine, arginine, asparagine; the human thrombin receptor "tethered ligand") induce neurite retraction and neurotoxicity. Because of the strong similarities between thrombin receptor and PAR-2, we have proposed that PAR-2 may also participate in neurodegeneration. In the present study, we used reverse transcriptase polymerase chain reaction and immunocytochemistry to provide the first evidence that PAR-2 is present in the rat hippocampus. Moreover, we found SLIGRL to be toxic to hippocampal neurons in a concentration-dependent manner (> or = 100 microM). Calcium signaling studies were performed to aid in determining the mechanism by which PAR-2 activation is neurotoxic.
Smith-Swintosky
V L
VL
R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477-0776, U.S.A.
Cheo-Isaacs
C T
CT
D'Andrea
M R
MR
Santulli
R J
RJ
Darrow
A L
AL
Andrade-Gordon
P
P
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017931:DNA Primers; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D051381:Rats; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000502:physiology; D018179:Receptors, Thrombin / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology
D000906:Antibodies; D017931:DNA Primers; D009842:Oligopeptides; D010446:Peptide Fragments; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; C082835:thrombin receptor peptide (42-47); D014357:Trypsin; D013917:Thrombin; D002118:Calcium