Regulation of dense core vesicle trafficking and capture by synaptotagmin 4
Final Report Abstract
Dense core vesicles in neurons transport and release neurotrophins and neuropeptides. These substances are important for many brain functions, including metabolism, pain perception and cognition. In neurons, dense core vesicles are filled with cargo in the cell body and must then travel long distances throughout neuronal processes where they accumulate at synapses - the connections between neurons. Delivery of neurotrophins and neuropeptides via long-range trafficking of dense core vesicles is essential for synapse modulation and circuit function. Neuropeptides are released during neuronal activity to strengthen synapses and circuits. But how dense core vesicles are captured at specific sites is unknown. We previously identified Synaptotagmin4 (Syt4) as an integral vesicle protein present on brain-derived neurotrophic factor (BDNF)-harboring dense core vesicles in neurons. Here we discovered that Syt4 regulates the spatial distribution and capture of dense core vesicles at specific sites in hippocampal neurons. We found that dense core vesicles are highly mobile and undergo long-range continual trafficking from the cell body to distal ends of neuronal processes and back again in a circular pattern. Modification of a specific amino acid of Syt4, Serine 135, by phosphorylation by c-Jun N-terminal kinase (JNK), destabilizes the interaction of Syt4 with Kinesin family member 1A (Kif1A), a motor protein present on microtubules, which leads Syt4-harboring dense core vesicles to transition from microtubule-dependent trafficking to capture at synaptic sites by actin. Neuronal activity increases dense core vesicle capture via this system of JNK-dependent phosphorylation of the S135 site of Syt4. Our data reveal a mechanism that ensures rapid, site-specific delivery of dense core vesicles to synapses, where they release neurotrophins and neuropeptides that are important to strengthen synapses and circuits.
Publications
- Capture of dense core vesicles at synapses by JNK- dependent phosphorylation of synaptotagmin-4. Cell Rep. 2017 Nov 21;21(8):2118-2133
Bharat V, Siebrecht M, Burk K, Ahmed S, Reissner C, Kohansal-Nodehi M, Steubler V, Zweckstetter M, Ting JT, Dean C
(See online at https://doi.org/10.1016/j.celrep.2017.10.084)
