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

Journal of Cell Science 2019 Februrary 2
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, 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 ubiquitination of the postsynaptic density protein-95 (PSD-95) and the removal of GluR1-containing α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors (AMPAR) from the PSD. These results show that the interaction between tPA and synaptic NMDA receptors regulates the expression of AMPA receptor sub-units 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.

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