Tissue-Type Plasminogen Activator Triggers the Synaptic Vesicle Cycle in Cerebral Cortical Neurons. Issue 12 (December 2015)

• Record Type: Journal Article
• Authors: Wu, Fang; Torre, Enrique; Cuellar-Giraldo, David; Cheng, Lihong; Yi, g; Bichler, Edyta K; García, Paul S; Yepes, Manuel
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 35:Issue 12(2015)
• Page Start: 1966
• Page End: 1976
• Publication Date: 2015-12
• Subjects: active zone -- cerebral ischemia -- plasticity -- synaptic vesicles -- tissue-type plasminogen activator; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1038/jcbfm.2015.155
• Languages: English
• ISSNs: 0271-678X

Abstract

The active zone (AZ) is a thickening of the presynaptic membrane where exocytosis takes place. Chemical synapses contain neurotransmitter-loaded synaptic vesicles (SVs) that at rest are tethered away from the synaptic release site, but after the presynaptic inflow of Ca +2 elicited by an action potential translocate to the AZ to release their neurotransmitter load. We report that tissue-type plasminogen activator (tPA) is stored outside the AZ of cerebral cortical neurons, either intermixed with small clear-core vesicles or in direct contact with the presynaptic membrane. We found that cerebral ischemia-induced release of neuronal tPA, or treatment with recombinant tPA, recruits the cytoskeletal protein βII-spectrin to the AZ and promotes the binding of SVs to βII-spectrin, enlarging the population of SVs in proximity to the synaptic release site. This effect does not require the generation of plasmin and is followed by the recruitment of voltage gated calcium channels (VGCC) to the presynaptic terminal that leads to Ca +2 -dependent synapsin I phosphorylation, freeing SVs to translocate to the AZ to deliver their neurotransmitter load. Our studies indicate that tPA activates the SV cycle and induces the structural and functional changes in the synapse that are required for successful neurotransmission.