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  • The full length human CPG protein


    The full-length human CPG2 protein is expressed in CNS tissue with the highest expression in the neocortex, hippocampus and striatum, consistent with mRNA localization patterns of the rat Cpg2 homolog (Cottrell et al., 2004). In the rat, the CPG2 protein localizes primarily to the postsynaptic endocytic zone of excitatory synapses, where it is required for the internalization of glutamate receptors (Cottrell et al., 2004). Here we show the existence of human CPG2 transcripts and their protein products in the human brain, and conserved human CPG2 function in glutamate receptor internalization. Interestingly, several independent lines of evidence, including GWAS have implicated abnormal glutamatergic activity in the neuronal impairments affecting patients with BD (Ferreira et al., 2008, Nurnberger et al., 2014, Psychiatric, G.C.B.D.W.G., 2011, Sanacora et al., 2008). Notably, SNPs in GRIA2, which encode the GluA2 subunit of AMPARs, have been associated with time to recurrence of mood episodes in BD patients on lithium (Perlis et al., 2009). Studies have also shown differences in glutamate levels as well as glutamate receptor expression or function between individuals with mood disorders and control subjects (Beneyto and Meador-Woodruff, 2006, McCullumsmith et al., 2007, Meador-Woodruff et al., 2001, Nudmamud-Thanoi and Reynolds, 2004, Scarr et al., 2003). The other major BD risk gene identified by GWAS (Cross-Disorder Group of the Psychiatric Genomics, C, 2013, Ferreira et al., 2008), ANK3, encodes the RG7227 sale cytoskeleton-associated adaptor protein ankyrin-G, which is also implicated in glutamate receptor-mediated synaptic transmission as well as the maintenance of RG7227 sale mature spine morphology (Smith et al., 2014). Furthermore, Ank3 has been shown to regulate lithium-attenuated psychiatric-related behaviors in mice (Leussis et al., 2013). Transcriptional mapping of the SYNE1 gene, focusing on the CPG2 region, is a first step towards clarifying which of its transcripts and protein products are likely to play a role in BD. Identification of a full-length CPG2 transcript expressed in human brain encoding a protein that is functionally conserved between rat and human, provides a platform for future testing of missense SNPs identified by BD patient exome sequencing for a role in glutamatergic transmission.
    Conflicts of interest
    Introduction Clathrin-mediated endocytosis (CME) of postsynaptic glutamate receptors is central for implementing long-term depression (LTD) and other forms of synaptic plasticity [1]. CME requires functional and temporal orchestration of numerous participating endocytic proteins. There is significant evidence that, in mammalian cells, CME relies on an active F-actin cytoskeleton at various stages in the life cycle of an endocytic vesicle (reviewed in [2, 3]). Despite the demonstrated functional link between F-actin and CME, little is known about the mechanisms underlying the coupling of these modules. Endocytic proteins, such as Hip-1 and dynamin, are known to interact indirectly with the actin cytoskeleton [4, 5], whereas others can associate with actin nucleating factors (reviewed in [2, 6]). However, none of these interactions were shown to be required for CME of synaptic glutamate receptors. Candidate plasticity gene 2 (CPG2) is an activity-regulated gene product of Syne1, enriched at endocytic zones within dendritic spines [7]. PKA-dependent association of CPG2 with F-actin is required for glutamate receptor internalization [8]. Here, we identify a direct physical interaction between CPG2 and EndoB2 and show that, by recruitment of this previously uncharacterized component of the endocytic machinery, CPG2 tethers the endocytic apparatus to the F-actin cytoskeleton in dendritic spines. We further show that this interaction is essential specifically for activity-dependent, but not constitutive, internalization of synaptic glutamate receptors.