Tissue-type plasminogen activator regulates p35-mediated Cdk5 activation in the postsynaptic terminal

• Type of Material: Article
• Authors: Ariel Diaz, Emory University; Valerie Jeanneret Lopez, Emory University; Paola Merino, Emory University; Patrick McCann, Emory University; Manuel Yepes, Emory University
• Language: English
• Date: 2019-03-01
• Publisher: The Company of Biologists
• Publication Version: Final Published Version
• Copyright Statement: © 2019. Published by The Company of Biologists Ltd.
• Final Published Version (URL): http://dx.doi.org/10.1242/jcs.224196
• Title of Journal or Parent Work: Journal of Cell Science
• Volume: 132
• Issue: 5
• Start Page: 1
• End Page: 9
• Grant/Funding Information: This work was supported by the National Heart, Lung, and Blood Institute [NS-091201 to M.Y.], the National Institute of Neurological Disorders and Stroke [NS-079331 to M.Y.] and the U.S. Department of Veterans Affairs [VA Merit Award I01BX003441 to M.Y.].
• Keywords: Neuronal Plasticity; Phosphotransferases; Protein Binding; NMDA receptors; Mice, Inbred C57BL; Cerebral Cortex; Cyclin-dependent kinase-5; Receptors, N-Methyl-D-Aspartate; Presynaptic Terminals; Animals; Tissue Plasminogen Activator; Neurons; Mice; Ubiquitination; Proteolysis; Tissue-type plasminogen activator; Disks Large Homolog 4 Protein; Receptors, AMPA; Plasmin; Postsynaptic density; Cells, Cultured; Cyclin-Dependent Kinase 5; Enzyme Activation
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience; Biology, Cell

Abstract

Neuronal depolarization induces the synaptic release of tissue-type plasminogen activator (tPA). Cyclin-dependent kinase-5 (Cdk5) is a member of the family of cyclin-dependent kinases that regulates cell migration and synaptic function in postmitotic neurons. Cdk5 is activated by its binding to p35 (also known as Cdk5r1), a membrane-anchored protein that is rapidly degraded by the proteasome. Here, we show that tPA prevents the degradation of p35 in the synapse by a plasminogen-dependent mechanism that requires open synaptic N-methyl-D-aspartate (NMDA) receptors. We show that tPA treatment increases the abundance of p35 and its binding to Cdk5 in the postsynaptic density (PSD). Furthermore, our data indicate that tPA-induced p35-mediated Cdk5 activation does not induce cell death, but instead prevents NMDA-induced ubiquitylation of postsynaptic density protein-95 (PSD-95; also known as Dlg4) and the removal of GluR1 (also known as Gria1)-containing α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors from the PSD. These results show that the interaction between tPA and synaptic NMDA receptors regulates the expression of AMPA receptor subunits in the PSD via p35-mediated Cdk5 activation. This is a novel role for tPA as a regulator of Cdk5 activation in cerebral cortical neurons.