title: Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation.
abstract: The secreted glycoprotein reelin plays an indispensable role in neuronal migration during development and in regulating adult synaptic functions. The upstream mechanisms responsible for initiating and regulating the duration and magnitude of reelin signaling are largely unknown. Here we report that reelin is cleaved between EGF-like repeats 6-7 (R6-7) by tissue plasminogen activator (tPA) under cell-free conditions. No changes were detected in the level of reelin and its fragments in the brains of tPA knockouts, implying that other unknown proteases are responsible for generating reelin fragments found constitutively in the adult brain. Induction of NMDAR-independent long-term potentiation with the potassium channel blocker tetraethylammonium chloride (TEA-Cl) led to a specific up-regulation of reelin processing at R6-7 in wild-type mice. In contrast, no changes in reelin expression and processing were observed in tPA knockouts following TEA-Cl treatment. These results demonstrate that synaptic potentiation results in tPA-dependent reelin processing and suggest that extracellular proteolysis of reelin may regulate reelin signaling in the adult brain.
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, United States; USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, United States.
authors.forename: J H
authors.initials: JH
authors.lastname: Trotter
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, United States; USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, United States.
authors.forename: A L
authors.initials: AL
authors.lastname: Lussier
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, United States; USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, United States.
authors.forename: K E
authors.initials: KE
authors.lastname: Psilos
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, United States; USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, United States.
authors.forename: H L
authors.initials: HL
authors.lastname: Mahoney
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, United States; USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, United States.
authors.forename: A E
authors.initials: AE
authors.lastname: Sponaugle
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, United States.
authors.forename: H-S
authors.initials: HS
authors.lastname: Hoe
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, United States.
authors.forename: G W
authors.initials: GW
authors.lastname: Rebeck
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33620, United States; USF Health Byrd Alzheimer's Institute, Tampa, FL 33613, United States. Electronic address: eweeber@health.usf.edu.
authors.forename: E J
authors.initials: EJ
authors.lastname: Weeber
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D059748:Proteolysis; D011994:Recombinant Proteins / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology; D046509:Tissue Culture Techniques; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; D000091042:Reelin Protein; D019789:Tetraethylammonium; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D010959:Tissue Plasminogen Activator
keywords: Hippocampus; Long-term potentiation; Reelin; Tetraethylammonium chloride; Tissue plasminogen activator (tPA)