Dataset Information

Capture of Dense Core Vesicles at Synapses by JNK-Dependent Phosphorylation of Synaptotagmin-4.

ABSTRACT: Delivery of neurotrophins and neuropeptides via long-range trafficking of dense core vesicles (DCVs) from the cell soma to nerve terminals is essential for synapse modulation and circuit function. But the mechanism by which transiting DCVs are captured at specific sites is unknown. Here, we discovered that Synaptotagmin-4 (Syt4) regulates the capture and spatial distribution of DCVs in hippocampal neurons. We found that DCVs are highly mobile and undergo long-range translocation but switch directions only at the distal ends of axons, revealing a circular trafficking pattern. Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction, leading to a transition from microtubule-dependent DCV trafficking to capture at en passant presynaptic boutons by actin. Furthermore, neuronal activity increased DCV capture via JNK-dependent phosphorylation of the S135 site of Syt4. Our data reveal a mechanism that ensures rapid, site-specific delivery of DCVs to synapses.

SUBMITTER: Bharat V

PROVIDER: S-EPMC5714612 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

Capture of Dense Core Vesicles at Synapses by JNK-Dependent Phosphorylation of Synaptotagmin-4.

Bharat Vinita V Siebrecht Michael M Burk Katja K Ahmed Saheeb S Reissner Carsten C Kohansal-Nodehi Mahdokht M Steubler Vicky V Zweckstetter Markus M Ting Jonathan T JT Dean Camin C

Cell reports 20171101 8

Delivery of neurotrophins and neuropeptides via long-range trafficking of dense core vesicles (DCVs) from the cell soma to nerve terminals is essential for synapse modulation and circuit function. But the mechanism by which transiting DCVs are captured at specific sites is unknown. Here, we discovered that Synaptotagmin-4 (Syt4) regulates the capture and spatial distribution of DCVs in hippocampal neurons. We found that DCVs are highly mobile and undergo long-range translocation but switch direc ...[more]

PMID: 29166604

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Project description:Release of neuropeptides from dense core vesicles (DCVs) is essential for neuromodulation. Compared with the release of small neurotransmitters, much less is known about the mechanisms and proteins contributing to neuropeptide release. By optogenetics, behavioral analysis, electrophysiology, electron microscopy, and live imaging, we show that synapsin SNN-1 is required for cAMP-dependent neuropeptide release in Caenorhabditis elegans hermaphrodite cholinergic motor neurons. In synapsin mutants, behaviors induced by the photoactivated adenylyl cyclase bPAC, which we previously showed to depend on ACh and neuropeptides (Steuer Costa et al., 2017), are altered as in animals with reduced cAMP. Synapsin mutants have slight alterations in synaptic vesicle (SV) distribution; however, a defect in SV mobilization was apparent after channelrhodopsin-based photostimulation. DCVs were largely affected in snn-1 mutants: DCVs were ∼30% reduced in synaptic terminals, and their contents not released following bPAC stimulation. Imaging axonal DCV trafficking, also in genome-engineered mutants in the serine-9 protein kinase A phosphorylation site, showed that synapsin captures DCVs at synapses, making them available for release. SNN-1 colocalized with immobile, captured DCVs. In synapsin deletion mutants, DCVs were more mobile and less likely to be caught at release sites, and in nonphosphorylatable SNN-1B(S9A) mutants, DCVs traffic less and accumulate, likely by enhanced SNN-1 dependent tethering. Our work establishes synapsin as a key mediator of neuropeptide release.SIGNIFICANCE STATEMENT Little is known about mechanisms that regulate how neuropeptide-containing dense core vesicles (DCVs) traffic along the axon, how neuropeptide release is orchestrated, and where it occurs. We found that one of the longest known synaptic proteins, required for the regulation of synaptic vesicles and their storage in nerve terminals, synapsin, is also essential for neuropeptide release. By electrophysiology, imaging, and electron microscopy in Caenorhabditis elegans, we show that synapsin regulates this process by tethering the DCVs to the cytoskeleton in axonal regions where neuropeptides are to be released. Without synapsin, DCVs cannot be captured at the release sites and, consequently, cannot fuse with the membrane, and neuropeptides are not released. We suggest that synapsin fulfills this role also in vertebrates, including humans.

Dataset Information

Capture of Dense Core Vesicles at Synapses by JNK-Dependent Phosphorylation of Synaptotagmin-4.

Publications

Capture of Dense Core Vesicles at Synapses by JNK-Dependent Phosphorylation of Synaptotagmin-4.

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