The simplistic idea that seven transmembrane receptors are single monomeric proteins that interact with heterotrimeric G-proteins after agonist binding is definitively out of date. Indeed, GPCRs (G-protein-coupled receptors) are part of multiprotein networks organized around scaffolding proteins. These GIPs (GPCR-interacting proteins) are either transmembrane or cytosolic proteins. Proteomic approaches can be used to get global pictures of these 'receptosomes'. This approach allowed us to identify direct but also indirect binding partners of serotonin receptors. GIPs are involved in a wide range of functions including control of the targeting, trafficking and signalling of GPCRs. One of them, Shank, which is a secondary and tertiary partner of metabotropic and ionotropic glutamate receptors, respectively, can induce the formation of a whole functional glutamate 'receptosome' and the structure to which it is associated, the dendritic spine.
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ACKR3 Proximity Labeling Identifies Novel G protein- and β-arrestin-independent GPCR Interacting Proteins.
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Department of Biochemistry, Duke University, Durham, NC, 27710, USA.
The canonical paradigm of GPCR signaling recognizes G proteins and β-arrestins as the two primary transducers that promote GPCR signaling. Recent evidence suggests the atypical chemokine receptor 3 (ACKR3) does not couple to G proteins, and β-arrestins are dispensable for some of its functions. Here, we employed proximity labeling to identify proteins that interact with ACKR3 in cells devoid of β-arrestin.
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Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany.
The original paradigm of classical - also referred to as canonical - cellular signal transduction of heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction of three players: the agonist-activated G protein-coupled receptor (GPCR), which activates the transducing G protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended by the identification of regulators and adapters such as the regulators of G protein signaling (RGS), receptor kinases like βARK, or GPCR-interacting arrestin adapters that are integrated into this canonical signaling process at different levels to enable fine-tuning. Finally, the identification of atypical signaling mechanisms of classical regulators, together with the discovery of novel modulators, added a new and fascinating dimension to the cellular G protein signal transduction.
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Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, B-3000, Leuven, Belgium.
Background: The human CXC chemokine receptor 2 (CXCR2) is a G protein-coupled receptor (GPCR) interacting with multiple chemokines (i.e., CXC chemokine ligands CXCL1-3 and CXCL5-8).
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Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York (I.B.K., E.L., T.P.S.); Tri-Institutional PhD Program in Chemical Biology, New York, New York (I.B.K.); Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH-Royal Institute of Technology, Solna, Sweden (J.M.S.); Department of Pharmacology and Toxicology, School of Biomedical Sciences, Division of Health Sciences, University of Otago, Dunedin, New Zealand (D.L.H.); and Department of Neurobiology, Care Sciences and Society (NVS), Division for Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Solna, Sweden (T.P.S.)
G protein-coupled receptors (GPCRs) are known to interact with several other classes of integral membrane proteins that modulate their biology and pharmacology. However, the extent of these interactions and the mechanisms of their effects are not well understood. For example, one class of GPCR-interacting proteins, receptor activity-modifying proteins (RAMPs), comprise three related and ubiquitously expressed single-transmembrane span proteins.
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Department of Infection and Immunity, Immuno-Pharmacology and Interactomics, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg; Department of Oncology, Tumor Immunotherapy and Microenvironment, Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg.
G protein-coupled receptor kinases (GRKs) are a family of seven soluble receptor-modifying enzymes which are essential regulators of GPCR activity. Following agonist-induced receptor activation and G protein dissociation, GRKs prime the receptor for desensitization through phosphorylation of its C terminus, which subsequently allows arrestins to bind and initiate the receptor internalization process. While GRKs constitute key GPCR-interacting proteins, to date, no method has been put forward to readily and systematically determine the preference of a specific GPCR towards the seven different GRKs (GRK1-7).
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