RGD Reference Report - CAPS and Munc13 utilize distinct PIP2-linked mechanisms to promote vesicle exocytosis. - Rat Genome Database

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CAPS and Munc13 utilize distinct PIP2-linked mechanisms to promote vesicle exocytosis.

Authors: Kabachinski, G  Yamaga, M  Kielar-Grevstad, DM  Bruinsma, S  Martin, TF 
Citation: Kabachinski G, etal., Mol Biol Cell. 2014 Feb;25(4):508-21. doi: 10.1091/mbc.E12-11-0829. Epub 2013 Dec 19.
RGD ID: 11535098
Pubmed: PMID:24356451   (View Abstract at PubMed)
PMCID: PMC3923642   (View Article at PubMed Central)
DOI: DOI:10.1091/mbc.E12-11-0829   (Journal Full-text)

Phosphoinositides provide compartment-specific signals for membrane trafficking. Plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) is required for Ca(2+)-triggered vesicle exocytosis, but whether vesicles fuse into PIP2-rich membrane domains in live cells and whether PIP2 is metabolized during Ca(2+)-triggered fusion were unknown. Ca(2+)-dependent activator protein in secretion 1 (CAPS-1; CADPS/UNC31) and ubMunc13-2 (UNC13B) are PIP2-binding proteins required for Ca(2+)-triggered vesicle exocytosis in neuroendocrine PC12 cells. These proteins are likely effectors for PIP2, but their localization during exocytosis had not been determined. Using total internal reflection fluorescence microscopy in live cells, we identify PIP2-rich membrane domains at sites of vesicle fusion. CAPS is found to reside on vesicles but depends on plasma membrane PIP2 for its activity. Munc13 is cytoplasmic, but Ca(2+)-dependent translocation to PIP2-rich plasma membrane domains is required for its activity. The results reveal that vesicle fusion into PIP2-rich membrane domains is facilitated by sequential PIP2-dependent activation of CAPS and PIP2-dependent recruitment of Munc13. PIP2 hydrolysis only occurs under strong Ca(2+) influx conditions sufficient to activate phospholipase Ceta2 (PLCeta2). Such conditions reduce CAPS activity and enhance Munc13 activity, establishing PLCeta2 as a Ca(2+)-dependent modulator of exocytosis. These studies provide a direct view of the spatial distribution of PIP2 linked to vesicle exocytosis via regulation of lipid-dependent protein effectors CAPS and Munc13.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of exocytosis involved_inIMP 11535098; 11535098PMID:24356451ParkinsonsUK-UCL 

Cellular Component
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
dense core granule located_inIDA 11535098PMID:24356451ParkinsonsUK-UCL 

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
phosphatidylinositol-4,5-bisphosphate binding enablesTAS 11535098PMID:24356451ParkinsonsUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Cadps  (calcium dependent secretion activator)
Unc13b  (unc-13 homolog B)


Additional Information