Arrestin-Dependent and -Independent Internalization of G Protein–Coupled Receptors: Methods, Mechanisms, and Implications on Cell Signaling
| Autor: | Thor C. Møller, Ee Von Moo, Jeffrey R. van Senten, Hans Bräuner-Osborne |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cell signaling media_common.quotation_subject Endocytosis Pathway Endocytosis Clathrin Receptors G-Protein-Coupled 03 medical and health sciences 0302 clinical medicine Arrestin Animals Humans Internalization G protein-coupled receptor media_common Pharmacology biology Chemistry Signal transducing adaptor protein Cell biology 030104 developmental biology biology.protein Molecular Medicine sense organs 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Moo, E V, Van Senten, J R, Bräuner-osborne, H & Møller, T C 2021, ' Arrestin-Dependent and-Independent Internalization of G Protein–Coupled Receptors: Methods, Mechanisms, and Implications on Cell Signaling ', Molecular Pharmacology, vol. 99, no. 4, pp. 242-255 . https://doi.org/10.1124/molpharm.120.000192 Molecular Pharmacology |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/molpharm.120.000192 |
| Popis: | Agonist-induced endocytosis is a key regulatory mechanism for controlling the responsiveness of the cell by changing the density of cell surface receptors. In addition to the role of endocytosis in signal termination, endocytosed G protein-coupled receptors (GPCRs) have been found to signal from intracellular compartments of the cell. Arrestins are generally believed to be the master regulators of GPCR endocytosis by binding to both phosphorylated receptors and adaptor protein 2 (AP-2) or clathrin, thus recruiting receptors to clathrin-coated pits to facilitate the internalization process. However, many other functions have been described for arrestins that do not relate to their role in terminating signaling. Additionally, there are now more than 30 examples of GPCRs that internalize independently of arrestins. Here we review the methods, pharmacological tools, and cellular backgrounds used to determine the role of arrestins in receptor internalization, highlighting their advantages and caveats. We also summarize key examples of arrestin-independent GPCR endocytosis in the literature and their suggested alternative endocytosis pathway (e.g., the caveolae-dependent and fast endophilin-mediated endocytosis pathways). Finally, we consider the possible function of arrestins recruited to GPCRs that are endocytosed independently of arrestins, including the catalytic arrestin activation paradigm. Technological improvements in recent years have advanced the field further, and, combined with the important implications of endocytosis on drug responses, this makes endocytosis an obvious parameter to include in molecular pharmacological characterization of ligand-GPCR interactions. SIGNIFICANCE STATEMENT: G protein-coupled receptor (GPCR) endocytosis is an important means to terminate receptor signaling, and arrestins play a central role in the widely accepted classical paradigm of GPCR endocytosis. In contrast to the canonical arrestin-mediated internalization, an increasing number of GPCRs are found to be endocytosed via alternate pathways, and the process appears more diverse than the previously defined "one pathway fits all." |
| Databáze: | OpenAIRE |
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