Abstract

G protein–coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain–containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role in regulating receptor and channel protein localization within synapses and tight junctions and function to scaffold intracellular signaling protein complexes. In the current study, we review the known functional interactions between PDZ domain–containing proteins and GPCRs and provide insight into the potential mechanisms of action. These PDZ domain–containing proteins include the membrane-associated guanylate-like kinases [postsynaptic density protein of 95 kilodaltons; synapse-associated protein of 97 kilodaltons; postsynaptic density protein of 93 kilodaltons; synapse-associated protein of 102 kilodaltons; discs, large homolog 5; caspase activation and recruitment domain and membrane-associated guanylate-like kinase domain-containing protein 3; membrane protein, palmitoylated 3; calcium/calmodulin-dependent serine protein kinase; membrane-associated guanylate kinase protein (MAGI)-1, MAGI-2, and MAGI-3], Na⁺/H⁺ exchanger regulatory factor proteins (NHERFs) (NHERF1, NHERF2, PDZ domain–containing kidney protein 1, and PDZ domain–containing kidney protein 2), Golgi-associated PDZ proteins (Gα-binding protein interacting protein, C-terminus and CFTR-associated ligand), PDZ domain–containing guanine nucleotide exchange factors (GEFs) 1 and 2, regulator of G protein signaling (RGS)–homology-RhoGEFs (PDZ domain–containing RhoGEF and leukemia-associated RhoGEF), RGS3 and RGS12, spinophilin and neurabin-1, SRC homology 3 domain and multiple ankyrin repeat domain (Shank) proteins (Shank1, Shank2, and Shank3), partitioning defective proteins 3 and 6, multiple PDZ protein 1, Tamalin, neuronal nitric oxide synthase, syntrophins, protein interacting with protein kinase C α 1, syntenin-1, and sorting nexin 27.