Phosphorylation of Doc2 by EphB2 modulates Munc13-mediated SNARE complex assembly and neurotransmitter release

At the synapse, presynaptic neurotransmitter release is tightly controlled by release machinery, involving the soluble -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and Munc13. The Ca sensor Doc2 cooperates with Munc13 to regulate neurotransmitter release, but the und...

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Bibliographic Details
Published in:Science advances 2024-05, Vol.10 (20), p.eadi7024-eadi7024
Main Authors: Zhang, Hong, Lei, Mengshi, Zhang, Yu, Li, Hao, He, Zhen, Xie, Sheng, Zhu, Le, Wang, Shen, Liu, Jianfeng, Li, Yan, Lu, Youming, Ma, Cong
Format: Article
Language:English
Subjects:
Animals
Biophysics
Calcium-Binding Proteins - metabolism
Cellular Neuroscience
Humans
Mice
Nerve Tissue Proteins - metabolism
Neuroscience
Neurotransmitter Agents - metabolism
Phosphorylation
Protein Binding
Rats
Receptor, EphB2 - genetics
Receptor, EphB2 - metabolism
SciAdv r-articles
SNARE Proteins - metabolism
Synaptic Transmission
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Summary:At the synapse, presynaptic neurotransmitter release is tightly controlled by release machinery, involving the soluble -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and Munc13. The Ca sensor Doc2 cooperates with Munc13 to regulate neurotransmitter release, but the underlying mechanisms remain unclear. In our study, we have characterized the binding mode between Doc2 and Munc13 and found that Doc2 originally occludes Munc13 to inhibit SNARE complex assembly. Moreover, our investigation unveiled that EphB2, a presynaptic adhesion molecule (SAM) with inherent tyrosine kinase functionality, exhibits the capacity to phosphorylate Doc2. This phosphorylation attenuates Doc2 block on Munc13 to promote SNARE complex assembly, which functionally induces spontaneous release and synaptic augmentation. Consistently, application of a Doc2 peptide that interrupts Doc2-Munc13 interplay impairs excitatory synaptic transmission and leads to dysfunction in spatial learning and memory. These data provide evidence that SAMs modulate neurotransmitter release by controlling SNARE complex assembly.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adi7024