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

Several studies have shown that both neuronal and glial cells express functional thrombin receptors as well as prothrombin transcripts. Recently, we (and others) have shown that alpha-thrombin induces apoptotic cell death in different neuronal cell types, including motoneurons, in culture. Thrombin-induced effects on different cells are mediated through the cell surface protease-activated thrombin receptor, PAR-1. Furthermore, it has been shown that, in contrast to thrombin, which induces proteolysis of other proteins besides its receptor, the thrombin receptor agonist peptide, serine-phenylalanine-leucine-leucine-arginine-asparagine-proline (SFLLRNP), is only known to activate this receptor. However, whether activation of the thrombin receptor in vivo affects the development of spinal cord motoneurons is not known. Here, we show that treatment with a synthetic SFLLRNP peptide induced a dose-dependent degeneration and death of spinal motoneurons both in highly enriched cultures and in the developing chick embryo in vivo. However, cotreatment with caspase inhibitors completely abolished SFLLRNP-induced motoneuron death both in vitro and in vivo. These results suggest that developing motoneurons express functionally active PAR-1 whose activation leads to cell death through stimulation of the caspase family of proteins. Our findings also suggest a novel and deleterious role for PAR-like receptors in the central nervous system, different from their previously known functions in the vascular and circulatory system.