PDZ Domain Containing Proteins

To date, the best characterized proteins involved in the scaffolding of multiprotein complexes that are involved in the targeting, trafficking, and signaling of GPCRs are PSD-95/Disc large/Zonula occludens-1 (PDZ) domain-containing proteins (Nourry et al. 2003). 5-HT2C receptors contain a C-terminal sequence (SSV) corresponding to one of the class 1 PDZ recognition motifs (X-S/T-X-I/L/V). A multi-PDZ domain adaptor protein (MUPP1), which contains 13 PDZ domains, was the first 5-HT2C receptor-interacting protein identified using the yeast two-hybrid system (Ullmer et al. 1998). The C-terminus of the 5-HT2C receptor selectively interacts with the 10th PDZ domain of MUPP1, and this interaction leads to a conformational change in MUPP1 (Becamel et al. 2001). Deletion of the 5-HT2C receptor PDZ recognition motif prevents phosphorylation of the receptor and delays resen-sitization of receptor responses in NIH 3 T3 fibroblasts, suggesting that interaction between MUPP1 and the 5-HT2C receptor is functionally significant (Backstrom et al. 2000). Thus, it was suggested that MUPP1 might function as a multivalent scaffold protein, which selectively assembles and targets 5-HT2C receptor-signaling complexes (Becamel et al. 2001). Further, using a proteomic approach based on peptide affinity chromatography followed by mass spectrometry and/or immunob-lotting, Becamel et al. identified at least 15 additional proteins that interact with the C-terminal tail of 5-HT2C receptors, including scaffold proteins that contain one or several PDZ domains, such as the Veli3 (vertebrate homologue of the Caenorabdis elegans PDZ protein Lin7), postsynaptic density protein 95 (PSD95), and MPP3 protein of the membrane-associated guanylate kinases (MAGUK) p55 subfamily (Becamel et al. 2002). These studies revealed the connection of 5-HT2C receptors to PDZ proteins exhibiting both presynaptic and postsynaptic localizations consistent with the differential distribution of the receptors at the synaptic junction. Thus, via association with Veli3, the 5-HT2C receptor interacts with the tripartite Veli3-CASK-Mint1 complex, which is located at the postsynaptic density, as well as with the presynaptic Veli3-CASK-Mint-Munc18 complex. Several studies using 5-HT2C receptors mutated on the PDZ recognition site show that interactions with PDZ proteins have a critical role in modulating signaling properties of 5-HT2C receptors and their desensitization (Backstrom et al. 2000; Gavarini et al. 2006). PSD95 and MPP3 proteins, the main PDZ-binding partners of the 5-HT2C receptor, appear to differentially modulate desensitization of receptor-associated Ca2+ responses in both heterologous cells and cultured cortical neurons, indicating that the functional activity of 5-HT2C receptors is modulated according to the repertoire of PDZ proteins coexpressed with the receptor (Gavarini et al. 2006).

Interestingly, the 5-HT2A and 5-HT2C receptors, two closely related GPCRs that share an identical canonical PDZ ligand, interact with distinct sets of PDZ proteins, which may contribute to their differences in signal transduction pathways (Becamel et al. 2004).

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