Tyrosine phosphorylation of the transmembrane protein SIRPα: Sensing synaptic activity and regulating ectodomain cleavage for synapse maturation
| Autor: | Erin M. Johnson-Venkatesh, Sivapratha Nagappan-Chettiar, Hisashi Umemori |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Patch-Clamp Techniques Primary Cell Culture Synaptogenesis Mice Transgenic Hippocampus Synaptic Transmission Biochemistry Potassium Chloride Synapse Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains Neurobiology Memory Postsynaptic potential Animals Humans Phosphorylation Receptors Immunologic Molecular Biology Janus Kinases Neurons Tissue Inhibitor of Metalloproteinases Tyrosine phosphorylation Cell Biology Cell biology Mice Inbred C57BL src-Family Kinases 030104 developmental biology chemistry Ectodomain Proteolysis Synapses Tyrosine Protein Processing Post-Translational 030217 neurology & neurosurgery Synapse maturation Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of Biological Chemistry. 293:12026-12042 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra117.001488 |
| Popis: | Synapse maturation is a neural activity–dependent process during brain development, in which active synapses preferentially undergo maturation to establish efficient neural circuits in the brain. Defects in this process are implicated in various neuropsychiatric disorders. We have previously reported that a postsynaptic transmembrane protein, signal regulatory protein-α (SIRPα), plays an important role in activity-dependently directing synapse maturation. In the presence of synaptic activity, the ectodomain of SIRPα is cleaved and released and then acts as a retrograde signal to induce presynaptic maturation. However, how SIRPα detects synaptic activity to promote its ectodomain cleavage and synapse maturation is unknown. Here, we show that activity-dependent tyrosine phosphorylation of SIRPα is critical for SIRPα cleavage and synapse maturation. We found that during synapse maturation and in response to neural activity, SIRPα is highly phosphorylated on its tyrosine residues in the hippocampus, a structure critical for learning and memory. Tyrosine phosphorylation of SIRPα was necessary for SIRPα cleavage and presynaptic maturation, as indicated by the fact that a phosphorylation-deficient SIRPα variant underwent much less cleavage and could not drive presynaptic maturation. However, SIRPα phosphorylation did not affect its synaptic localization. Finally, we show that inhibitors of the Src and JAK kinase family suppress neural activity–dependent SIRPα phosphorylation and cleavage. Together, our results indicate that SIRPα phosphorylation serves as a mechanism for detecting synaptic activity and linking it to the ectodomain cleavage of SIRPα, which in turn drives synapse maturation in an activity-dependent manner. |
| Databáze: | OpenAIRE |
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