title: Brefeldin A-inhibited guanine nucleotide exchange protein 3 is localized in lysosomes and regulates GABA signaling in hippocampal neurons.
abstract: ADP-ribosylation factor (ARF) family of guanine-nucleotide-binding (G) proteins regulates organelle biogenesis, structure and trafficking. The functions of ARF proteins are tightly controlled by guanine nucleotide exchange factors (GEFs) containing a conserved SEC7 domain. Based on sequence similarity to brefeldin A-inhibited guanine nucleotide exchange protein (BIG)/GBF of the Arf-GEF family, we recently identified BIG3 as a novel ARF GEF protein with a non-functional catalytic motif in the SEC7 domain. BIG3 is mainly expressed in pancreatic islets and brain. In the islets, depletion of BIG3 increases insulin and glucagon secretion because of enhanced biogenesis of insulin and glucagon granules in the absence of BIG3. Here, we investigate BIG3 functions in the brain, in particular its regulation of neurotransmitter release in hippocampal neurons from wild-type and BIG3 knockout mice. In hippocampal neurons, BIG3 is mainly localized in lysosomes, and its depletion selectively impairs inhibitory synaptic transmission. Our finding provides novel insights for a cell-specific function of BIG3 in regulating neurotransmission.
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis* / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology*; D008247:Lysosomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: C000595370:ARFGEF3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D005680:gamma-Aminobutyric Acid
keywords: GABA; IPSC; brefeldin A-inhibited guanine nucleotide exchange protein 3; exocytosis; lysosome