Combining RNAi and Immunofluorescence Approaches to Investigate Post-endocytic Sorting of GPCRs into Multivesicular Bodies

Li, Xuezhi; Rosciglione, Stéphanie; Laniel, Andréanne; Lavoie, Christine

doi:10.1007/978-1-4939-9121-1_17

Cited by 3 publications

(1 citation statement)

References 17 publications

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“…The study of the further processing of these complexes showed that they are first internalized and transported to early endosomes. Then, the GPCRs are either recycled back to the plasma membrane in an active, ligand-free state, or they are sorted within the endocytic pathway and packaged into intraluminal vesicles, forming multivesicular bodies that fuse with lysosomes, and this leads to complete degradation of the receptors [ 27 , 28 ]. At the turn of 1990–2000, the participation of β-arrestins in GPCR-mediated regulation of the mitogen-activated protein kinases (MAPKs) and several other effector proteins and transcription factors were demonstrated [ 21 , 24 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators of GPCRs are simple ions, various biomolecules, and protein components of GPCR signaling (G proteins and β-arrestins). The stability and functional activity of GPCR complexes is also due to multicenter allosteric interactions between protomers. The complexity of allosteric effects caused by numerous regulators differing in structure, availability, and mechanisms of action predetermines the multiplicity and different topology of allosteric sites in GPCRs. These sites can be localized in extracellular loops; inside the transmembrane tunnel and in its upper and lower vestibules; in cytoplasmic loops; and on the outer, membrane-contacting surface of the transmembrane domain. They are involved in the regulation of basal and orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, and endocytosis. They are targets for a large number of synthetic allosteric regulators and modulators, including those constructed using molecular docking. The review is devoted to the principles and mechanisms of GPCRs allosteric regulation, the multiplicity of allosteric sites and their topology, and the endogenous and synthetic allosteric regulators, including autoantibodies and pepducins. The allosteric regulation of chemokine receptors, proteinase-activated receptors, thyroid-stimulating and luteinizing hormone receptors, and beta-adrenergic receptors are described in more detail.

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Section: Introductionmentioning

confidence: 99%

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

2023

IJMS

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Allosteric Sites and Allosteric Regulators of G Protein-Coupled Receptors: Gray Cardinals of Signal Transduction

Shpakov

2023

J Evol Biochem Phys

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Allosteric Sites and Allosteric Regulators of G-Protein-Coupled Receptors: Gray Cardinals of Signal Transduction

Shpakov

2023

Žurnal èvolûcionnoj biohimii i fiziologii

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Membrane G protein-coupled receptors (GPCRs) are key components of most eukaryotic signaling systems, transducing external signals to intracellular effector proteins. Activation of GPCRs occurs through the specific binding of ligands of different nature to their orthosteric site. However, regulation of the affinity of an orthosteric agonist for the receptor, control of its effectiveness, and selection of the preferentially activated intracellular signaling cascade is carried out using allosteric mechanisms. This is due to the presence in GPCRs of many allosteric sites, which differ in structural and functional organization and topology in the receptor molecule, and are located in all its functional subdomains. The endogenous regulators of these sites are simple ions (Na+, Zn2+, Mg2+, Ca2+, Cl– and others), lipids (cholesterol, phospholipids, steroids), amino acids and their derivatives, polypeptides, as well as signaling proteins that form functionally active complexes with GPCRs (G proteins, β‑arrestins, RAMPs), and autoantibodies to the extracellular regions of GPCRs. Based on pharmacological activity, ligands of allosteric sites of GPCRs are divided into positive, negative or silent modulators of the effects of orthosteric agonists, as well as full and inverse agonists or neutral antagonists, which affect the basal activity of the receptor in the absence of an orthosteric agonist, although combining the properties of a modulator and an agonist is also possible. The multiplicity of allosteric sites and allosteric regulators, complex interactions between them, and the involvement of allosteric mechanisms in the formation of receptor complexes play a key role in fine-tuning the functional activity of signaling cascades, in biased agonism, and predetermine the processes of receptor desensitization and the fate of the receptor complex after hormonal signal transduction. The review summarizes and analyzes current concepts and new trends in the field of studying the allosteric regulation of GPCRs, the localization and functional role of allosteric sites, and their endogenous and synthetic ligands. As an example, synthetic allosteric regulators of the receptors of thyroid-stimulating and luteinizing hormones, as potential drugs for the correction of endocrine disorders, are discussed in detail.

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Combining RNAi and Immunofluorescence Approaches to Investigate Post-endocytic Sorting of GPCRs into Multivesicular Bodies

Cited by 3 publications

References 17 publications

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

Allosteric Sites and Allosteric Regulators of G Protein-Coupled Receptors: Gray Cardinals of Signal Transduction

Allosteric Sites and Allosteric Regulators of G-Protein-Coupled Receptors: Gray Cardinals of Signal Transduction

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