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The secretory granule-associated protein CAPS2 regulates neurotrophin release and cell survival.

ABSTRACT: Neurotrophins are key modulators of various neuronal functions, including differentiation, survival, and synaptic plasticity, but the molecules that regulate their secretion are poorly understood. We isolated a clone that is predominantly expressed in granule cells of postnatally developing mouse cerebellum, which turned out to be a paralog of CAPS (Ca2+-dependent activator protein for secretion), and named CAPS2. CAPS2 is enriched on vesicular structures of presynaptic parallel fiber terminals of granule cells connecting postsynaptic spines of Purkinje cell dendrites. Vesicle factions affinity-purified by the CAPS2 antibody from mouse cerebella contained significant amounts of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and chromogranin B but not marker proteins for synaptic vesicle synaptophysin and synaptotagmin. In cerebellar primary cultures, punctate CAPS2 immunoreactivities are primarily colocalized with those of NT-3 and BDNF and near those of a postsynaptic marker, postsynaptic density-95, around dendritic arborization of Purkinje cells. Exogenously expressed CAPS2 enhanced release of exogenous NT-3 and BDNF from PC12 cells and endogenous NT-3 from cultured granule cells in a depolarization-dependent manner. Moreover, the overexpression of CAPS2 in granule cells promotes the survival of Purkinje cells in cerebellar cultures. Thus, we suggest that CAPS2 mediates the depolarization-dependent release of NT-3 and BDNF from granule cells, leading to regulation in cell differentiation and survival during cerebellar development.

SUBMITTER: Sadakata T

PROVIDER: S-EPMC6729559 | biostudies-literature | 2004 Jan

REPOSITORIES: biostudies-literature

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The secretory granule-associated protein CAPS2 regulates neurotrophin release and cell survival.

Sadakata Tetsushi T Mizoguchi Akira A Sato Yumi Y Katoh-Semba Ritsuko R Fukuda Mitsunori M Mikoshiba Katsuhiko K Furuichi Teiichi T

The Journal of neuroscience : the official journal of the Society for Neuroscience 20040101 1

Neurotrophins are key modulators of various neuronal functions, including differentiation, survival, and synaptic plasticity, but the molecules that regulate their secretion are poorly understood. We isolated a clone that is predominantly expressed in granule cells of postnatally developing mouse cerebellum, which turned out to be a paralog of CAPS (Ca2+-dependent activator protein for secretion), and named CAPS2. CAPS2 is enriched on vesicular structures of presynaptic parallel fiber terminals ...[more]

PMID: 14715936

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Project description:The type 2 Ca2+-dependent activator protein for secretion (CAPS2/CADPS2) regulates dense-core vesicle trafficking and exocytosis and is involved in the regulated release of catecholamines, peptidergic hormones, and neuromodulators. CAPS2 is expressed in the pancreatic exocrine acinar cells that produce and secrete digestive enzymes. However, the functional role of CAPS2 in vesicular trafficking and/or exocytosis of non-regulatory proteins in the exocrine pancreas remains to be determined. Here, we analyzed the morpho-pathological indicators of the pancreatic exocrine pathway in Cadps2-deficient mouse models using histochemistry, biochemistry, and electron microscopy. We used whole exosome sequencing to identify CADPS2 variants in patients with chronic pancreatitis (CP). Caps2/Cadps2-knockout (KO) mice exhibited morphophysiological abnormalities in the exocrine pancreas, including excessive accumulation of secretory granules (zymogen granules) and their amylase content in the cytoplasm, deterioration of the fine intracellular membrane structures (disorganized rough endoplasmic reticulum, dilated Golgi cisternae, and the appearance of empty vesicles and autophagic-like vacuoles), as well as exocrine pancreatic cell injury, including acinar cell atrophy, increased fibrosis, and inflammatory cell infiltration. Pancreas-specific Cadps2 conditional KO mice exhibited pathological abnormalities in the exocrine pancreas similar to the global Cadps2 KO mice, indicating that these phenotypes were caused either directly or indirectly by CAPS2 deficiency in the pancreas. Furthermore, we identified a rare variant in the exon3 coding region of CADPS2 in a non-alcoholic patient with CP and showed that Cadps2-dex3 mice lacking CAPS2 exon3 exhibited symptoms similar to those exhibited by the Cadps2 KO and cKO mice. These results suggest that CAPS2 is critical for the proper functioning of the pancreatic exocrine pathway, and its deficiency is associated with a risk of pancreatic acinar cell pathology.

Dataset Information

The secretory granule-associated protein CAPS2 regulates neurotrophin release and cell survival.

Publications

The secretory granule-associated protein CAPS2 regulates neurotrophin release and cell survival.

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