The ADP ribosylation factor proteins are a family of six small, ubiquitously expressed GTP binding proteins. Of these, Arf6 localizes primarily to the plasma membrane/endosomal process, and is best known as a regulator of endocytic trafficking and actin cytoskeleton natural product libraries dynamics. In hippocampal neurons, Arf6 has been demonstrated to control axonal outgrowth, dendritic arborization, dendritic spine development, and the assembly of clathrin/AP2 buildings at synaptic membranes. The human genome contains 15 Arf GEFs, which catalyze the exchange of GDP for GTP via the evolutionarily conserved catalytic Sec7 domain. The Brefeldin A Resistant Arf GEFs comprise a subfamily of three proteins that are abundantly expressed within the postsynaptic density. BRAG2/IQSec1 has recently been shown to interact directly with the cytoplasmic domain of the AMPA R subunit GluA2, and to control its synaptic task dependent endocytosis. In comparison, BRAG1/IQSec2 is reported to connect to NMDA Rs, however not AMPA Rs, through an indirect process relating to the synaptic scaffolding protein PSD 95. Lately, Shoubridge et Cellular differentiation al. . identified four nonsynonymous single nucleotide polymorphisms in BRAG1 from people with nonsyndromic X linked intellectual disabilility. Three of the SNPs resulted in nonconserved amino acid substitutions within the catalytic Sec7 site, as the next was an alternative within an IQ motif. Here we report that BRAG1 posseses an integral role in synaptic transmission. We show that expression of exogenous BRAG1 in CA1 hippocampal neurons leads to depression of AMPA Dtc mediated synaptic transmission, in a way dependent upon upstream NMDA R activation. This depression can be influenced by BRAG1 catalytic action, indicating that it takes Arf6 Dovitinib molecular weight activation. . We demonstrate that BRAG1 binds calmodulin, and that a mutation within the IQ motif that stops CaM binding results in constitutive depression of AMPA Kiminas mediated transmission. More over, BRAG1 seems to selectively control the trafficking of GluA1 containing AMPA Rs by stimulating JNK signaling. Together, these results indicate that BRAG1 functions as a calmodulin responsive switch to manage AMPA Kiminas signaling downstream of NMDA R activation. The reagents found in this study include APV, NMDA, ionomycin, Bapta AM, and calmodulin sepharose 4B. Principal antibodies used were 16B12 HA, 9E10 Myc, GFP, and PSD 95. BRAG1 rabbit antiserum was raised against a peptide, corresponding to proteins 258 275, coupled to key-hole limpet hemocyanin as antigen. Human BRAG1 cDNA was obtained in the Kasuza DNA Research Institute. The coding sequence of BRAG1 was subcloned in to pCMV3A Myc using HindIII/ XhoI. The BRAG1 E849K and BRAG1 IQ mutants were produced by site directed mutagenesis. The BRAG1 N mutant was produced by digesting BRAG1 WT with EcoRV/ NruI which creates an in frame deletion of the N terminal 213 amino-acids. BRAG1 was digested out of pCMV3A Myc using HindIII/XhoI, and ligated in to mCherry C2 using HindIII/SalI, to create Cherry marked types.