Proteolysis of cell adhesion molecules by serine proteases: a role in long term potentiation?
Tissue plasminogen activator (tPA), a serine protease endogenous to hippocampal neurons, is shown to recognize a highly conserved sequence in the extracellular domain of cell adhesion molecules (CAMs). When added to brain homogenates, tPA generated a CAM fragment similar in size to that produced in hippocampal slices by brief periods of NMDA receptor stimulation. The serine protease inhibitor 4-(2-Aminoethyl)-benzenesulfonyl fluoride blocked the effects of tPA with an approximately 50% suppression at 250 microM. The inhibitor at this concentration had no evident effect on synaptic responses but caused long term potentiation to decay back to baseline over a 1 h period. These results suggest that extracellular breakdown of cell adhesion molecules initiated by NMDA receptors and mediated by serine proteases contributes to the formation of stable potentiation.
Hoffman
K B
KB
Ancile Pharmaceuticals, 1250 Prospect Street, Suite 202, La Jolla, CA 92037, USA.
Martinez
J
J
Lynch
G
G
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006868:Hydrolysis; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology*; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D013450:Sulfones; D014361:Trypsin Inhibitors; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D012697:Serine Endopeptidases; D010959:Tissue Plasminogen Activator