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 α‐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 (≥100 µM). Calcium signaling studies were performed to aid in determining the mechanism by which PAR‐2 activation is neurotoxic.