Brefeldin A‐inhibited guanine nucleotide exchange protein 3 is localized in lysosomes and regulates GABA signaling in hippocampal neurons

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 ( GEF s) containing a conserved SEC 7 domain. Based on sequence similarity to brefeldin A‐inhibited guanine nucleotide exchange protein ( BIG )/ GBF of the Arf‐ GEF family, we recently identified BIG 3 as a novel ARF GEF protein with a non‐functional catalytic motif in the SEC 7 domain. BIG 3 is mainly expressed in pancreatic islets and brain. In the islets, depletion of BIG 3 increases insulin and glucagon secretion because of enhanced biogenesis of insulin and glucagon granules in the absence of BIG 3. Here, we investigate BIG 3 functions in the brain, in particular its regulation of neurotransmitter release in hippocampal neurons from wild‐type and BIG 3 knockout mice. In hippocampal neurons, BIG 3 is mainly localized in lysosomes, and its depletion selectively impairs inhibitory synaptic transmission. Our finding provides novel insights for a cell‐specific function of BIG 3 in regulating neurotransmission.