CAPS-1 promotes fusion competence of stationary dense-core vesicles in presynaptic terminals of mammalian neurons

Farina, Margherita; Bospoort, Rhea van de; He, Enqi; Persoon, Claudia M.; Weering, Jan R.T. van; Broeke, Jurjen H.; Verhage, Matthijs; Toonen, Ruud F.

doi:10.7554/elife.05438

Cited by 51 publications

(80 citation statements)

References 62 publications

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“…DCVs can be released extra-synaptically, including along axons following robust stimulation protocols (Bospoort et al 2012; Matsuda et al, 2009), and CAPS1 is required for DCV fusion from extrasynaptic sites in mammalian neurons (Farina et al, 2015). Future work will provide important insight into the intrinsic axonal changes, including calcium-dependent mechanisms, that may promote DCV and neuropeptide release after injury.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

et al. 2016

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Neuronal injury triggers robust responses from glial cells, including altered gene expression and enhanced phagocytic activity to ensure prompt removal of damaged neurons. The molecular underpinnings of glial responses to trauma remain unclear. Here, we find that the evolutionarily conserved Insulin-like signaling (ILS) pathway promotes glial phagocytic clearance of degenerating axons in adult Drosophila. We find that the Insulin-like Receptor (InR) and downstream effector Akt1 are acutely activated in local ensheathing glia after axotomy, and are required for proper clearance of axonal debris. InR/Akt1 activity is also essential for injury-induced activation of STAT92E and its transcriptional target draper, which encodes a conserved receptor essential for glial engulfment of degenerating axons. Increasing Draper levels in adult glia partially rescues delayed clearance of severed axons in glial InR-inhibited flies. We propose that ILS functions as a key post-injury communication relay to activate glial responses, including phagocytic activity.

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Section: Discussionmentioning

confidence: 99%

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

et al. 2016

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“…Consequently, CAPS proteins are expressed in selective tissues, such as the pancreas, adrenal gland, and brain (Speidel et al, 2003, 2005, 2008). Knockout of CAPS1 in mice induced a reduction in DCV release, leading to neonatal death soon after birth (Farina et al, 2015; Speidel et al, 2005), which indicates that CAPS1 is required for efficient DCV exocytosis. Among the multiple steps required for exocytosis, CAPS1 promotes the priming reaction, which is a required step for the fusion of vesicles with the plasma membrane after docking has occurred (Farina et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Knockout of CAPS1 in mice induced a reduction in DCV release, leading to neonatal death soon after birth (Farina et al, 2015; Speidel et al, 2005), which indicates that CAPS1 is required for efficient DCV exocytosis. Among the multiple steps required for exocytosis, CAPS1 promotes the priming reaction, which is a required step for the fusion of vesicles with the plasma membrane after docking has occurred (Farina et al, 2015). Membrane fusion is mediated by the trans -SNARE (Soluble NSF attachment protein receptor) complex, which is composed of the vesicle SNARE (v-SNARE) and target membrane SNARE (t-SNARE).…”

Section: Introductionmentioning

confidence: 99%

CAPS1 RNA Editing Promotes Dense Core Vesicle Exocytosis

et al. 2016

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SUMMARY Calcium-dependent activator protein for secretion 1 (CAPS1) plays a distinct role in the priming step of dense core vesicle (DCV) exocytosis. CAPS1 pre-mRNA is known to undergo adenosine-to-inosine RNA editing in its coding region, which results in a glutamate-to-glycine conversion at a site in its C-terminal region. However, the physiological significance of CAPS1 RNA editing remains elusive. Here, we created mutant mice in which edited CAPS1 was solely expressed. These mice were lean due to increased energy expenditure caused by physical hyperactivity. Electrophysiological and biochemical analyses demonstrated that the exocytosis of DCVs was upregulated in the chromaffin cells and neurons of these mice. Furthermore, we showed that edited CAPS1 bound preferentially to the activated form of syntaxin-1A, a component of the exocytotic fusion complex. These findings suggest that RNA editing regulates DCV exocytosis in vivo, affecting physical activity.

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“…Beyond that, a few studies have analyzed the role of CAPS1 in neurons. It has been shown very recently that CAPS1 increases the number of fusion-competent neuropeptide Y (NPY)-containing secretory granules in axons (Farina et al, 2015) and regulates synaptic vesicle exocytosis in cultured neurons (Jockusch et al, 2007). Furthermore, immunocytochemical detection has revealed decreased BDNF protein levels in the molecular layer of the cerebellum of conditional CAPS1-knockout mice (Sadakata et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…CAPS1 is expressed in several brain regions, including the cerebellum, cortex, hippocampus and olfactory bulb (Sadakata et al, 2006;Speidel et al, 2003). In hippocampal neurons, CAPS1 is localized in axons and dendrites (Farina et al, 2015;Sadakata et al, 2006), and is known to affect secretory granule exocytosis in neuroendocrine cells (Grishanin et al, 2004;Speidel et al, 2005Speidel et al, , 2008. Beyond that, a few studies have analyzed the role of CAPS1 in neurons.…”

Section: Introductionmentioning

confidence: 99%

CAPS1 effects on intragranular pH and regulation of BDNF release from secretory granules in hippocampal neurons

Eckenstaler

Leßmann

Brigadski

2016

Journal of Cell Science

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The secretory protein brain-derived neurotrophic factor (BDNF) is assumed to be a key factor for the induction of synaptic plasticity processes in neurons. However, the molecular mechanisms for activity-dependent release of the protein largely remain elusive. Here, we demonstrate the relevance of the priming factor CAPS1 (also known as CADPS) for the maturation and exocytosis of BDNFcontaining secretory granules, as well as for neurotransmitter release from synaptic vesicles. Using live-cell imaging and RNA silencing methods, we show that CAPS1 has a previously unrecognized function in regulating the intragranular pH of BDNF-containing secretory granules. Furthermore, our results demonstrate that acute single-cell knockdown of CAPS1 with unaltered expression in neighboring neurons leads to a strong reduction in the number of fusion-competent secretory granules and to a significant decrease of released BDNF following exocytosis in dendrites of CAPS1-deficient neurons. In addition, our results show a reduction in synaptic vesicle turnover after CAPS1 knockdown without affecting the density of active boutons in hippocampal neurons. Thus, our results reveal new functions of endogenous CAPS1 in the BDNF secretory granule life cycle, thereby representing a new mechanism of neuronal plasticity.

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CAPS-1 promotes fusion competence of stationary dense-core vesicles in presynaptic terminals of mammalian neurons

Cited by 51 publications

References 62 publications

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper

CAPS1 RNA Editing Promotes Dense Core Vesicle Exocytosis

CAPS1 effects on intragranular pH and regulation of BDNF release from secretory granules in hippocampal neurons

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