The Receptor Tyrosine Kinase Met and Its Ligand Hepatocyte Growth Factor are Clustered at Excitatory Synapses and Can Enhance Clustering of Synaptic Proteins

Abstract

The receptor protein tyrosine kinase Met and its ligand, hepatocyte growth factor, regulate cellular morphology, intercellular adhesion, and interactions among junctional proteins in numerous cell types. However, they have not been extensively studied in the central nervous system. We report that Met is clustered at excitatory synapses and that treatment of neurons with hepatocyte growth factor can enhance expression and clustering of synaptic proteins. We demonstrate that Met is present in clusters that strongly colocalize with the NR2B subunit of the N-methyl-D-aspartate receptor, PSD-95, and synapsin at excitatory synapses on hippocampal neurons in vitro. We also show that Met is clustered at the postsynaptic density of excitatory synapses in the CA1 region of the hippocampus with the use of immuno-electron microscopy. Hepatocyte growth factor also forms clusters that partially colocalize with PSD-95. Treatment of cultured neurons with exogenous hepatocyte growth factor increased expression of the NR2B subunit of the N-methyl-D-aspartate receptor, calcium/calmodulin-dependent protein kinase II, and the GluR1 subunit of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor. The size and number of clusters of these proteins were also increased at sites along dendrites in response to hepatocyte growth factor. These results suggest a novel role for Met and hepatocyte growth factor in regulating synapses.