Synaptic NMDA Page1=46 activation causes a rapid regional increase in Ca2 levels that’s crucial for the induction of synaptic plasticity. To check this concept, we incorporated SP600125, an inhibitor of JNK, or SB203580, which inhibits p38 MAPK, in culture media during expression of BRAG1 IQ and BRAG1 N. SP600125, but not SB203580, completely blocked the depressive effect of BRAG1 IQ and the potentiative effect of BRAG1 N in CA1 neurons, suggesting a selective involvement of JNK signaling. Fostamatinib Syk inhibitor In line with this concept, Western blots confirmed that expression of BRAG1 IQ increased levels of phosphorylated JNK in CA1 cells, while expression of BRAG1 N decreased JNK activation. . Notably neither construct influenced the degrees of p38 MAPK phosphorylation. Expression of BRAG1 IQ or BRAG1 N did not change the levels of overall JNK and p38. Collectively, these results show that BRAG1 Arf6 signs synaptic depression via stimulating JNK signaling, however not p38 MAPK signaling. P38MAPK and JNK push transmission by signaling synaptic removal of GluA2 and GluA1 containing AMPA Rs, respectively. To check whether BRAG1 Arf6 oversees synaptic trafficking of GluA1 and/or GluA2 containg AMPA Rs, we examined the results of BRAG1 mutants in CA1 neurons Mitochondrion prepared from GluA1 and GluA2 knockout mice. . As shown in Fig. 10, the depressive effect of BRAG1 IQ and potentiative effect of BRAG1 N were occluded or blocked in GluA1 but not GluA2 knockout CA1 neurons. These results claim that BRAG1 Arf6 signals synaptic melancholy via stimulating JNK mediated synaptic removal of GluA1 containing AMPA Rs. The Arf GEFs BRAG1, BRAG2 and BRAG3 are highly enriched in the mind, where they’re concentrated in postsynaptic densities. While all three BRAG family proteins are expressed in hippocampal neurons, BRAG3 localizes specifically for the PSDs of inhibitory synapses, whereas both BRAG2 and BRAG1 are found at excitatory synapses. While BRAG2 was recently demonstrated to determine mGluR dependent synaptic treatment of GluA2 containing AMPA Rs, the purpose of BRAG1, which is implicated in nonsyndromic HSP inhibitors X connected intellectual disabilility, hadn’t been investigated. Here we report that BRAG1 indicators synaptic depression of AMPA transmission in response to synaptic activation of NMDA Rs. We further show that diseaseassociated mutations, which affect either catalytic action or CaM binding, end up in either inhibition or constitutive activation of Arf6 signaling, respectively. Furthermore, while BRAG2 acts on GluA2 containing AMPARs, BRAG1 appears to selectively modulate GluA1 containing AMPAR mediated transmission through a procedure that requires the downstream activation of JNK. These findings provide new insight in to the machinery controlling AMPA R trafficking, and provide a mechanistic basis for the defects in learning and memory exhibited by patients with X linked intellectual disability. The IQ pattern is evolutionarily conserved among the BRAG family Arf GEFs, and this hadn’t been previously demonstrated, although it has been assumed to bind CaM.