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Description

IQ motif and SEC7 domain-containing protein 3 (UniProt: Q76M68, also known as Potential synaptic guanine nucleotide exchange factor for Arf, SynArfGEF-Po) is encoded by the Iqsec3 (also known as Sag) gene (Gene ID: 404781) in rat. IQSEC3 along with IQSEC1 and IQSEC2 constitutes a family of brefeldin A-resistant ARF guanine nucleotide exchange factors (GEFs). It is a cytoplasmic protein that is expressed in the brain and is localized to dendrites and soma. Its expression is reported as early as E18 in hippocampal neurons. It is a key factor in controlling network activity in the hippocampus under both physiological and pathological conditions. It is shown to be exclusively localized to inhibitory synapses and it directly binds to gephyrin to promote inhibitory synapse formation in an ARF-GEF activity-dependent manner. IQSEC3 is reported to regulate GABAergic synapse maintenance in vivo and it links gephyrin-GABAA receptor complexes with ARF-dependent pathways to prevent aberrant, runaway excitation. Knockdown of Iqsec3 gene in the hippocampal dentate gyrus (DG) induces a significant reduction in GABAergic synapse density and causes a massive reduction of somatostatin expression in the DG hilus. IQ domain of IQSEC3 is localized to amino acids 311-340, the SEC7 domain is in amino acids 646-838, and the PH domain is in amino acids 852-985. (Ref.: Kim, S., et al. (2020). Cell Rep. 30(6), 1995-2005, Um, JW., et al. (2016). J. Biol. Chem. 291(19), 10119-10130).