Characterization of the composition of the postsynaptic proteome (PSP) provides a framework for understanding the overall organization and function of the synapse in normal and pathological conditions. We have identified 698 proteins from the postsynaptic terminal of mouse CNS synapses using a series of purification strategies and analysis by liquid chromatography tandem mass spectrometry and large-scale immunoblotting. Some 620 proteins were found in purified postsynaptic densities (PSDs), nine in AMPA-receptor immuno-purifications, 100 in isolates using an antibody against the NMDA receptor subunit NR1, and 170 by peptide-affinity purification of complexes with the C-terminus of NR2B. Together, the NR1 and NR2B complexes contain 186 proteins, collectively referred to as membrane-associated guanylate kinase-associated signalling complexes. We extracted data from six other synapse proteome experiments and combined these with our data to provide a consensus on the composition of the PSP. In total, 1124 proteins are present in the PSP, of which 466 were validated by their detection in two or more studies, forming what we have designated the Consensus PSD. These synapse proteome data sets offer a basis for future research in synaptic biology and will provide useful information in brain disease and mental disorder studies.

GABA B receptors are heterodimeric G protein-coupled receptors that mediate slow synaptic inhibition in the central nervous system. Whereas heterodimerization between GABA B receptor GABA B R1 and GABA B R2 subunits is essential for functional expression, how neurons coordinate the assembly of these critical receptors remains to be established. Here we have identified Marlin-1, a novel GABA B receptor-binding protein that associates specifically with the GABA B R1 subunit in yeast, tissue culture cells, and neurons. Marlin-1 is expressed in the brain and exhibits a granular distribution in cultured hippocampal neurons. Marlin-1 binds different RNA species including the 3-untranslated regions of both the GABA B R1 and GABA B R2 mRNAs in vitro and also associates with RNA in cultured neurons. Inhibition of Marlin-1 expression via small RNA interference technology results in enhanced intracellular levels of the GABA B R2 receptor subunit without affecting the level of GABA B R1. Together our results suggest that Marlin-1 functions to regulate the cellular levels of GABA B R2 subunits, which may have significant effects on the production of functional GABA B receptor heterodimers. Therefore, our observations provide an added level of regulation for the control of GABA B receptor expression and for the efficacy of inhibitory synaptic transmission.It has become widely accepted that protein-protein interactions are responsible for the formation and maintenance of the signaling platforms that organize local transduction units (1). Protein associations have also been shown to modulate the synthesis, targeting, and stabilization of membrane receptors (2). The study of the spatial and temporal compartmentalization of G protein-coupled receptors (GPCRs) 1 is essential to understand the mechanisms for neuronal integration of multiple stimuli. The identification of signaling partners has been well documented for ion channels (3-5), but less is known about the proteins that assist GPCRs (6, 7). GABA B receptors mediate the slow and prolonged phase of synaptic inhibition (8) and, unlike other GPCRs, they require the formation of a heterodimer between GABA B R1 and GAB-A B R2 (9). These two subunits display high homology to metabotropic glutamate, Ca 2ϩ -sensing, vomeronasal, and putative pheromone receptors, and recombinant GABA B R1/GABA B R2 receptors mimic the effector-coupling and pharmacological properties of native receptors (10). Clinically, GABA B receptors have been implicated in depression, neuroprotection, and cognition, and the production of GABA B R1 knock-out mice has confirmed their role in epilepsy and pain (11,12). Furthermore, recent studies indicate that their activation may be beneficial in the treatment of withdrawal symptoms from addictive drugs (13). Given their critical role in synaptic transmission and their potential therapeutic implications, it is fundamental to understand all aspects of GABA B receptor signaling.The modulation of neuronal GABA B receptors is likely to occur at multiple levels rangi...

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