CAPS-1 and CAPS-2 Are Essential Synaptic Vesicle Priming Proteins

Jockusch, Wolf J.; Speidel, Dina; Sigler, Albrecht; Sørensen, Jakob B.; Varoqueaux, Frédérique; Rhee, Jeong−Seop; Brose, Nils

doi:10.1016/j.cell.2007.11.002

Cited by 190 publications

(289 citation statements)

References 49 publications

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“…This is reminiscent of the temporary reversal of the deficit in transmitter release in hippocampal neurons in CAPS DKO mice when extracellular calcium was raised (Jockusch et al, 2007). We tested whether secretion in CAPS DKO cells has a different calcium requirement than that of wild-type cells.…”

Section: Resultsmentioning

confidence: 99%

CAPS Facilitates Filling of the Rapidly Releasable Pool of Large Dense-Core Vesicles

Liu¹,

Schirra²,

Stevens³

et al. 2008

J. Neurosci.

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Calcium-activator protein for secretion (CAPS) is a cytosolic protein that associates with large dense-core vesicles and is involved in their secretion. Mammals express two CAPS isoforms, which share a similar domain structure including a Munc13 homology domain that is believed to be involved in the priming of secretory vesicles. A variety of studies designed to perturb CAPS function indicate that CAPS is involved in the secretion of large dense-core vesicles, but where in the secretory pathway CAPS acts is still under debate. Mice in which one allele of the CAPS-1 gene is deleted exhibit a deficit in catecholamine secretion from chromaffin cells. We have examined catecholamine secretion from chromaffin cells in which both CAPS genes were deleted and show that the deletion of both CAPS isoforms causes a strong reduction in the pool of rapidly releasable chromaffin granules and of sustained release during ongoing stimulation. We conclude that CAPS is required for the adequate refilling and/or maintenance of a rapidly releasable granule pool.

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Section: Resultsmentioning

confidence: 99%

CAPS Facilitates Filling of the Rapidly Releasable Pool of Large Dense-Core Vesicles

Liu¹,

Schirra²,

Stevens³

et al. 2008

J. Neurosci.

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“…UNC-31 is the C. elegans homolog of mammalian CAPS, a component of the DCV release machinery required for hormone and neuropeptide release from neuroendocrine cells (Walent et al 1992;Rupnik et al 2000). Although CAPS and its paralog CAPS-2 may have additional functions, including synaptic vesicle priming and catecholamine uptake into DCVs, the role of the only C. elegans CAPS homolog, UNC-31, specifically involves DCV docking in the process of exocytosis from neurons (Speidel et al 2005;Gracheva et al 2007;Jockusch et al 2007;Speese et al 2007;Zhou et al 2007;Hammarlund et al 2008). Drosophila CAPS function at the neuromuscular junction is also restricted to DCV exocytosis with additional cell nonautonomous effects on synaptic vesicle release believed to result from the lack of neuromodulators released from DCVs (Renden et al 2001).…”

Section: Discussionmentioning

confidence: 99%

UNC-73/Trio RhoGEF-2 Activity Modulates Caenorhabditis elegans Motility Through Changes in Neurotransmitter Signaling Upstream of the GSA-1/Gαs Pathway

Pawson

Steven

2011

Genetics

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Rho-family GTPases play regulatory roles in many fundamental cellular processes. Caenorhabditis elegans UNC-73 RhoGEF isoforms function in axon guidance, cell migration, muscle arm extension, phagocytosis, and neurotransmission by activating either Rac or Rho GTPase subfamilies. Multiple differentially expressed UNC-73 isoforms contain a Rac-specific RhoGEF-1 domain, a Rho-specific RhoGEF-2 domain, or both domains. The UNC-73E RhoGEF-2 isoform is activated by the G-protein subunit Ga q and is required for normal rates of locomotion; however, mechanisms of UNC-73 and Rho pathway regulation of locomotion are not clear. To better define UNC-73 function in the regulation of motility we used cell-specific and inducible promoters to examine the temporal and spatial requirements of UNC-73 RhoGEF-2 isoform function in mutant rescue experiments. We found that UNC-73E acts within peptidergic neurons of mature animals to regulate locomotion rate. Although unc-73 RhoGEF-2 mutants have grossly normal synaptic morphology and weak resistance to the acetylcholinesterase inhibitor aldicarb, they are significantly hypersensitive to the acetylcholine receptor agonist levamisole, indicating alterations in acetylcholine neurotransmitter signaling. Consistent with peptidergic neuron function, unc-73 RhoGEF-2 mutants exhibit a decreased level of neuropeptide release from motor neuron dense core vesicles (DCVs). The unc-73 locomotory phenotype is similar to those of rab-2 and unc-31, genes with distinct roles in the DCV-mediated secretory pathway. We observed that constitutively active Ga s pathway mutations, which compensate for DCV-mediated signaling defects, rescue unc-73 RhoGEF-2 and rab-2 lethargic movement phenotypes. Together, these data suggest UNC-73 RhoGEF-2 isoforms are required for proper neurotransmitter signaling and may function in the DCV-mediated neuromodulatory regulation of locomotion rate.

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“…CAPS, rabphilin, and Syt1 support exocytosis via interaction with PIP [53,65,79]. CAPS, a component of the synaptic vesicle priming machinery, maintains a fusion-competent vesicle pool for transmitter release [47]. Syt1 and rabphilin contain C2 domains, interacting with PI(4,5)P2 and PI(3,4,5)P3; although such interactions are suggested to mediate Ca 2+ -triggered merger [23,53], our data rule out a direct role for PIP in fusion.…”

Section: Roles For Polyphosphoinositides In Regulated Releasementioning

confidence: 99%

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

Rogasevskaia

Coorssen

2011

J Chem Biol

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Studies using isolated sea urchin cortical vesicles have proven invaluable in dissecting mechanisms of Ca 2+ -triggered membrane fusion. However, only acute molecular manipulations are possible in vitro. Here, using selective pharmacological manipulations of sea urchin eggs ex vivo, we test the hypothesis that specific lipidic components of the membrane matrix selectively affect defined late stages of exocytosis, particularly the Ca 2+ -triggered steps of fast membrane fusion. Egg treatments with cholesterol-lowering drugs resulted in the inhibition of vesicle fusion. Exogenous cholesterol recovered fusion extent and efficiency in cholesterol-depleted membranes; α-tocopherol, a structurally dissimilar curvature analogue, selectively restored fusion extent. Inhibition of phospholipase C reduced vesicle phosphatidylethanolamine and suppressed both the extent and kinetics of fusion. Although phosphatidylinositol-3-kinase inhibition altered levels of polyphosphoinositide species and reduced all fusion parameters, sequestering polyphosphoinositides selectively inhibited fusion kinetics. Thus, cholesterol and phosphatidylethanolamine play direct roles in the fusion pathway, contributing negative curvature. Cholesterol also organizes the physiological fusion site, defining fusion efficiency. A selective influence of phosphatidylethanolamine on fusion kinetics sheds light on the local microdomain structure at the site of docking/fusion. Polyphosphoinositides have modulatory upstream roles in priming: alterations in specific polyphosphoinositides likely represent the terminal priming steps defining fully docked, release-ready vesicles. Thus, this pharmacological approach has the potential to be a robust high-throughput platform to identify molecular components of the physiological fusion machine critical to docking, priming, and triggered fusion.

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CAPS-1 and CAPS-2 Are Essential Synaptic Vesicle Priming Proteins

Cited by 190 publications

References 49 publications

CAPS Facilitates Filling of the Rapidly Releasable Pool of Large Dense-Core Vesicles

CAPS Facilitates Filling of the Rapidly Releasable Pool of Large Dense-Core Vesicles

UNC-73/Trio RhoGEF-2 Activity Modulates Caenorhabditis elegans Motility Through Changes in Neurotransmitter Signaling Upstream of the GSA-1/Gαs Pathway

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

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