9 - Role of PDZ Proteins in Regulating Trafficking, Signaling, and Function of GPCRs: Means, Motif, and Opportunity
Introduction
G protein-coupled receptors (GPCRs) form the largest family of signaling receptors that are expressed in vertebrate cells. They are responsible for transducing a strikingly vast array of extracellular signals to biological actions. GPCRs represent 2% of the human genome and are important drug targets. Effectively, these receptors are guanine nucleotide exchange factors, which when occupied by their cognate ligand, exchange guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on the alpha subunit of the associated heterotrimeric nucleotide-binding protein. The activated alpha subunit then dissociates from the beta–gamma subunit. Signal transduction is mostly mediated by the alpha subunit but sometimes by the beta–gamma subunit pair. The two principal signaling pathways involved are by Gαs or inhibition by Gi of the adenylyl cyclase–cAMP–protein kinase A (PKA)/EPAC signaling pathway, and stimulation by Gαq of the phospholipase C (PLC)—Ca2+ + phosphatidylinositol pathway. GPCR desensitization provides a mechanism to protect cells against excessive stimulation, while GPCR resensitization guards cells against prolonged desensitization and hormone insensitivity. Desensitization and receptor internalization are the two primary mechanisms controlling GPCR signaling.
Although most receptors activate a single pathway, some receptors employ multiple signaling pathways. The type 1 parathyroid hormone receptor (PTH1R), for instance, in vascular smooth muscle cells, parathyroid hormone (PTH), stimulates adenylyl cyclase but not PLC (Maeda et al., 1996, Wu et al., 1993), whereas in keratinocytes (Orloff et al., 1995, Whitfield et al., 1992), cardiac myocytes (Rampe et al., 1991, Schlüter et al., 1995), and lymphocytes (Atkinson et al., 1987, Klinger et al., 1990, Whitfield et al., 1971), the PTH1R activates PLC but not adenylyl cyclase. In osteoblasts and kidney tubule cells, PTH activates both adenylyl cyclase and PLC (Abou-Samra et al., 1992, Friedman et al., 1996, Hruska et al., 1987). The origin of the cell-specific signaling remained obscure until the discovery that a PDZ adapter protein, present in some but not in all cells expressing the PTH1R switches signaling between adenylyl cyclase and PLC (Mahon et al., 2002). Increasing evidence now supports the view that cytoplasmic adapter proteins affect the signaling and trafficking of many GPCRs, and thereby their biological behavior. In this review, we describe emerging findings regarding the means by which modular PDZ proteins confer ligand- and cell-specific signaling and trafficking on select GPCRs, the corresponding recognition motifs engaged by the cognate proteins, and the physiological opportunities regulated by these interactions.
Section snippets
PDZ Proteins
PDZ proteins are soluble cytoplasmic adapter proteins that function as transient scaffolding structures to assemble multiprotein signaling complexes by virtue of highly conserved modules. The general arrangement for PDZ domains is based on the structure of PSD95, DLG, and ZO1, for which they are named. The human genome includes some 200–300 PDZ proteins. PDZ modules consist of an 80–90 amino acid sequence forming a three-dimensional globular structure that is composed of six β-sheets (βA–βF)
Family A GPCRs
Depending on how stringently one defines the consensus motif for PDZ-mediated protein interaction, a handful to a potentially large number of mammalian family A GPCRs have the ability to engage PDZ domain-containing proteins. Table III lists those family A GPCRs for which such interactions have been established most convincingly, and specifically linked to function.
G Proteins
Although we focus our discussion primarily on GPCRs interacting with PDZ proteins, it should be noted that several G proteins themselves have canonical or internal PDZ-recognition sequences that bind PDZ proteins. Both NHERF1 and NHERF2, for example, bind Gαq (Rochdi et al., 2002, Wang et al., 2010), and NHERF2, but not NHERF1, interacts with Gαi. Neither NHERF1 nor NHERF2 associates with Gαs. The ability of PDZ proteins to engage G proteins underscores their ability to act as molecular routers
Conclusion
Our understanding of multiprotein interactions and how they impart many of the characteristic features of GPCRs is a subject of intense investigation and consequently a rapidly changing arena. It is now clear that many of the heretofore irreconcilable reported findings between GPCR signaling, trafficking, and function in different cells or in response to distinct ligands now can be attributed to the participation of PDZ proteins and their ability to confer ligand- and cell-specific actions on
Acknowledgments
Original work conducted in the authors’ laboratories was supported by grants DK054171, DK069998 (PAF), and DA10711, DA12864 (MVZ) from the National Institutes of Health.
Conflict of Interest: The authors have no conflicts of interest to declare.
References (141)
- et al.
Deletion of the serotonin 5-HT2C receptor PDZ recognition motif prevents receptor phosphorylation and delays resensitization of receptor responses
The Journal of Biological Chemistry
(2000) - et al.
GABAB receptor association with the PDZ scaffold Mupp 1 alters receptor stability and function
The Journal of Biological Chemistry
(2007) - et al.
The carboxyl-terminal PDZ ligand motif of chemokine receptor CXCR2 modulates post-endocytic sorting and cellular chemotaxis
The Journal of Biological Chemistry
(2008) - et al.
Structure of the Homer EVH1 domain-peptide complex reveals a new twist in polyproline recognition
Neuron
(2000) - et al.
RAMP isoform-specific regulation of adrenomedullin receptor trafficking by NHERF-1
The Journal of Biological Chemistry
(2005) - et al.
Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains
Cell
(1996) - et al.
A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression
The Journal of Biological Chemistry
(2002) - et al.
Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL
The Journal of Biological Chemistry
(2004) - et al.
Dapper, a Dishevelled-associated antagonist of ß-catenin and JNK signaling, is required for notochord formation
Developmental Cell
(2002) - et al.
Binding of the ß2 adrenergic receptor to N-ethylmaleimide-sensitive factor regulates receptor recycling
The Journal of Biological Chemistry
(2001)
Crystal structures of a complexed and peptide-free membrane protein-binding domain: Molecular basis of peptide recognition by PDZ
Cell
The glucagon-like peptide-2 Receptor C terminus modulates ß-Arrestin-2 association but is dispensable for ligand-induced desensitization, endocytosis, and G-protein-dependent effector activation
The Journal of Biological Chemistry
Catching a GEF by its tail
Trends in Cell Biology
Assembly of an SAP97-AKAP79-cAMP-dependent protein kinase scaffold at the type 1 PSD-95/DLG/ZO1 motif of the human ß1-adrenergic receptor generates a receptosome involved in receptor recycling and networking
The Journal of Biological Chemistry
Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled
The Journal of Biological Chemistry
The PDZ protein mupp 1 promotes Gi coupling and signaling of the Mt1 melatonin receptor
The Journal of Biological Chemistry
G protein-coupled receptor kinase 6A phosphorylates the Na+/H+ exchanger regulatory factor via a PDZ domain-mediated interaction
The Journal of Biological Chemistry
Proteomic analysis of ß1-adrenergic receptor interactions with PDZ scaffold proteins
The Journal of Biological Chemistry
Direct interaction of Frizzled-1, -2, -4, and -7 with PDZ domains of PSD-95
FEBS Letters
GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR
The Journal of Biological Chemistry
κ Opioid receptor interacts with Na+/H+-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na+/H+ exchange independent of Gi/Go proteins
The Journal of Biological Chemistry
The interaction of phospholipase C-ß3 with Shank2 regulates mGluR-mediated calcium signal
The Journal of Biological Chemistry
Physiological actions of regulators of G-protein signaling (RGS) proteins
Life Sciences
Crystal structure of the PDZ1 domain of human Na+/H+ exchanger regulatory factor provides insights into the mechanism of carboxyl-terminal leucine recognition by class I PDZ domains
Journal of Molecular Biology
Tamalin is a scaffold protein that interacts with multiple neuronal proteins in distinct modes of protein-protein association
The Journal of Biological Chemistry
Effect of parathyroid hormone on human T cell activation
Kidney International
MAGI-3 competes with NHERF-2 to negatively regulate LPA(2) receptor signaling in colon cancer cells
Gastroenterology
Ezrin induces long-range interdomain allostery in the scaffolding protein NHERF1
Journal of Molecular Biology
Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate
The Journal of Biological Chemistry
Selectivity and promiscuity of the first and second PDZ domains of PSD-95 and synapse-associated protein 102
The Journal of Biological Chemistry
Interaction between the internal motif KTXXXI of Idax and mDvl PDZ domain
Biochemical and Biophysical Research Communications
Indole-2-amide based biochemical antagonist of Dishevelled PDZ domain interaction down-regulates Dishevelled-driven Tcf transcriptional activity
Bioorganic & Medicinal Chemistry Letters
Stimulation by parathyroid hormone of a NHERF-1-assembled complex consisting of the parathyroid hormone I receptor, PLCß, and actin increases intracellular calcium in opossum kidney cells
The Journal of Biological Chemistry
PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor
The Journal of Biological Chemistry
Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma
Journal of Hepatology
GABAB receptor coupling to G-proteins and ion channels
Advances in Pharmacology
The PDZ scaffold NHERF-2 interacts with mGluR5 and regulates receptor activity
The Journal of Biological Chemistry
The C terminus of the metabotropic glutamate receptor subtypes 2 and 7 specifies the receptor signaling pathways
The Journal of Biological Chemistry
Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: A single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium
Proceedings of the National Academy of Science of the United States of America
Nuclear trafficking of Drosophila Frizzled-2 during synapse development requires the PDZ protein dGRIP
Proceedings of the National Academy of Science of the United States of America
Parathyroid hormone stimulation of mitosis in rat thymic lymphocytes is independent of cyclic AMP
Journal of Bone and Mineral Research
MacMARCKS interacts with the metabotropic glutamate receptor type 7 and modulates G protein-mediated constitutive inhibition of calcium channels
Journal of Neurochemistry
PICK1 uncoupling from mGluR7a causes absence-like seizures
Nature Neuroscience
The post-endocytotic fate of the gonadotropin receptors is an important determinant of the desensitization of gonadotropin responses
Journal of Molecular Endocrinology
Serotonin receptor signaling and regulation via ß-arrestins
Critical Reviews in Biochemistry and Molecular Biology
Vangl2 directs the posterior tilting and asymmetric localization of motile primary cilia
Nature Cell Biology
Homer: A protein that selectively binds metabotropic glutamate receptors
Nature
A kinase-regulated PDZ-domain interaction controls endocytic sorting of the ß2-adrenergic receptor
Nature
The DIX domain targets dishevelled to actin stress fibres and vesicular membranes
Nature
A human exchange factor for ARF contains Sec7- and pleckstrin-homology domains
Nature
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