Interacting Partners. GPR37 and GPR37L1 contain a consensus PDZ binding motif, G-T-X-C, at their extreme C-termini (Xxxxxx et al. 2009). As previously described, PDZ domain-containing proteins are cytoplasmic scaffolding proteins capable of assembling diverse multiprotein signaling complexes. Interaction of PDZ proteins with GPCRs can impact the signaling, trafficking, and function of targeted receptors (Magalhaes, Dunn, and Xxxxxxxx 2012; Xxxx and Xxxxxxxx 2015). Several studies have described interactions with GPR37 and/or GPR37L1 and PDZ proteins, including syntenin-1 (Xxxxxx et al. 2009; Dutta et al. 2014), multi-PDZ domain protein 1 (MUPP1) (Tanabe et al. 2015), protein interacting with C-kinase (PICK1) and GRIP4/5 (Dutta et al. 2014). Co-expression of GPR37 with syntenin-1 dramatically increases total and surface receptor expression (Xxxxxx et al. 2009). Conversely, interaction with PICK1 reduces GPR37 expression levels (Dutta et al. 2014). However, the physiological relevance of these and other potential PDZ interactions remains to be determined. In addition to association with PDZ containing proteins, GPR37 and GPR37L1 form heterodimers. Dimerization can occur between two copies of the same monomer, homodimerization, or it can take the form of distinct monomer pairs, as in heterodimerization. GPCR dimerization can modify receptor expression, trafficking, ligand binding, G protein coupling, and downstream signaling. Studies have shown GPR37 and GPR37L1 to physically interact with the dopamine transporter (DAT) and dopaminergic receptors, D1 and D2 (Xxxxxx et al. 2009; Xxxxx 2014; Xxxxxxxxx et al. 2007). GPR37 co- immunoprecipitates with DAT in overexpressed HEK293 cells (Marazziti et al. 2007). Although no interaction in native tissues has been reported, both GPR37 and DAT are enriched in the presynaptic fraction of mouse striata, co-expression of GPR37 with the dopaminergic D2 receptor (D2R) increased GPR37 expression and enhanced D2R ligand affinity as measured by [3H]-spiperone competition binding assays (Xxxxxx et al. 2009). Furthermore, D2R ligands had reduced affinity in mice lacking GPR37 (Marazziti et al. 2007). In contrast to GPR37, physical association between GPR37L1 and D2R has not been reported. Xxxxxxx, XXX00X0 does associate with the dopamine D1 receptor (Xxxxx 2014). This interaction is not only detectable in overexpressed HEK293T cells, but in brain lysates as well, suggesting a physiologically relevant interaction. Interestingly, coexpression of the dop...
