Activation of the protease-activated thrombin receptor (PAR)-1 induces motoneuron degeneration in the developing avian embryo

Several studies have shown that both neuronal and glial cells express funct ional thrombin receptors as well as prothrombin transcripts. Recently, we ( and others) have shown that a-thrombin induces apoptotic cell death in diff erent neuronal cell types, including motoneurons, in culture. Thrombin-indu ced effects on different cells are mediated through the cell surface protea se-activated thrombin receptor, PAR-I. Furthermore, it has been shown that, in contrast to thrombin, which induces proteolysis of other proteins besid es its receptor, the thrombin receptor agonist peptide, serine-phenylalanin e-leucine leucine-arginine-asparagine-proline (SFLLRNP), is only known to a ctivate this receptor. However, whether activation of the thrombin receptor in vivo affects the development of spinal cord motoneurons is not known. H ere, we show that treatment with a synthetic SFLLRNP peptide induced a dose -dependent degeneration and death of spinal motoneurons both in highly enri ched cultures and in the developing chick: embryo in vivo. However, cotreat ment with caspase inhibitors completely abolished SFLLRNP-induced motoneuro n death both in vitro and in vivo. These results suggest that developing mo toneurons express functionally active PAR-1 whose activation leads to cell death through stimulation of the caspase family of proteins. Our findings a lso suggest a novel and deleterious role for PAR-like receptors in the cent ral nervous system, different from their previously known functions in the vascular and circulatory system.