Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression.

Dysfunction of the proteins regulating synaptic function can cause synaptic plasticity imbalance that underlies neurological disorders such as intellectual disability. A study found that four distinct mutations within BRAG1, an Arf-GEF synaptic protein, each led to X-chromosome-linked intellectual disability (XLID). Although the physiological functions of BRAG1 are poorly understood, each of these mutations reduces BRAG1's Arf-GEF activity.

Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines.

The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca(2+) permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca(2+) signaling is well established, the molecular target remains unknown.

Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability.

The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability.

BRAG1, a Sec7 domain-containing protein, is a component of the postsynaptic density of excitatory synapses.

The postsynaptic density (PSD) at excitatory synapses is a dynamic complex of glutamatergic receptors and associated proteins that governs synaptic structure and coordinates signal transduction. In this study, we report that BRAG1, a putative guanine nucleotide exchange factor for the Arf family of GTP-binding proteins, is a major component of the PSD. BRAG1 was identified in a 190 kDa band in the PSD fraction with the use of mass spectrometry coupled to searching of a protein sequence database.