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Special Issue "G Protein-Coupled Receptors in Cell Signaling Transduction"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 30 April 2023 | Viewed by 3786

Special Issue Editors

1. Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomic, Tübingen, Germany
2. Interfaculty Center for Pharmacogenomics and Drug Research, Eberhard Karls University Tübingen and University Clinic, Tübingen, Germany
Interests: G proteins; non-canonical signaling; cardiovascular diesease; immune responses
Special Issues, Collections and Topics in MDPI journals
Rudolf-Schönheimer-Institute for Biochemistry, University Leipzig, Leipzig, Germany
Interests: adipocytes; adhesion G protein-coupled receptors; GPCR; adhesion; mechano-activation; signal transduction; de-orphanisation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) and their downstream signaling pathways are critical targets for current pharmacotherapy. More than one-third of the drugs in use today act on GPCRs either as agonists, inverse agonists or antagonists. However, their therapeutic potential is not exhausted, especially since recent findings point to new pharmacotherapeutically relevant regulatory mechanisms. In particular, hitherto largely unknown non-classical or also termed non-canonical regulatory mechanisms of GPCR-signaling have been identified that can either modulate canonical signaling by G proteins or trigger unrelated signaling events. These pathways are governed by other receptor classes than GPCRs, and various non-receptor regulators, including activators of G protein signaling (AGS) proteins or phosphate transferring nucleoside diphosphate kinases (NDPKs). GPCR adapters such as arrestins and regulators of G protein signaling (RGS) can exert additional functions distinct from inactivation of G protein signaling. Original research articles, reviews, communications on the (patho)physiological relevance of canonical and non-canonical GPCR signaling in biological processes, such as tumor progression, autophagy and cell movement, which are crucial for major human diseases, including cancer, metabolic disorders, cardiovascular diseases, immune responses or (neuro-)sensory defects will be particularly appreciated.

Prof. Dr. Sandra Beer-Hammer
Prof. Dr. Ines Liebscher
Guest Editors

Manuscript Submission Information

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Keywords

  • GPCRs
  • G-Proteins
  • canonical/non-canonical signaling
  • AGS proteins
  • RGS proteins
  • β-arrestin
  • NDPKs
  • pharmacological intervention
  • biased ligands

Published Papers (5 papers)

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Research

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Article
Altered Intracellular Signaling Associated with Dopamine D2 Receptor in the Prefrontal Cortex in Wistar Kyoto Rats
Int. J. Mol. Sci. 2023, 24(6), 5941; https://doi.org/10.3390/ijms24065941 - 21 Mar 2023
Viewed by 236
Abstract
Wistar-Kyoto rats (WKY), compared to Wistar rats, are a well-validated animal model for drug-resistant depression. Thanks to this, they can provide information on the potential mechanisms of treatment-resistant depression. Since deep brain stimulation in the prefrontal cortex has been shown to produce rapid [...] Read more.
Wistar-Kyoto rats (WKY), compared to Wistar rats, are a well-validated animal model for drug-resistant depression. Thanks to this, they can provide information on the potential mechanisms of treatment-resistant depression. Since deep brain stimulation in the prefrontal cortex has been shown to produce rapid antidepressant effects in WKY rats, we focused our study on the prefrontal cortex. Using quantitative autoradiography, we observed a decrease in the binding of [3H] methylspiperone to the dopamine D2 receptor, specifically in that brain region—but not in the striatum, nor the nucleus accumbens—in WKY rats. Further, we focused our studies on the expression level of several components associated with canonical (G proteins), as well as non-canonical, D2-receptor-associated intracellular pathways (e.g., βarrestin2, glycogen synthase kinase 3 beta—Gsk-3β, and β-catenin). As a result, we observed an increase in the expression of mRNA encoding the regulator of G protein signaling 2-RGS2 protein, which is responsible, among other things, for internalizing the D2 dopamine receptor. The increase in RGS2 expression may therefore account for the decreased binding of the radioligand to the D2 receptor. In addition, WKY rats are characterized by the altered signaling of genes associated with the dopamine D2 receptor and the βarrestin2/AKT/Gsk-3β/β-catenin pathway, which may account for certain behavioral traits of this strain and for the treatment-resistant phenotype. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors in Cell Signaling Transduction)
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Article
Role of Monomer/Tetramer Equilibrium of Rod Visual Arrestin in the Interaction with Phosphorylated Rhodopsin
Int. J. Mol. Sci. 2023, 24(5), 4963; https://doi.org/10.3390/ijms24054963 - 04 Mar 2023
Viewed by 562
Abstract
The phototransduction cascade in vertebrate rod visual cells is initiated by the photoactivation of rhodopsin, which enables the activation of the visual G protein transducin. It is terminated by the phosphorylation of rhodopsin, followed by the binding of arrestin. Here we measured the [...] Read more.
The phototransduction cascade in vertebrate rod visual cells is initiated by the photoactivation of rhodopsin, which enables the activation of the visual G protein transducin. It is terminated by the phosphorylation of rhodopsin, followed by the binding of arrestin. Here we measured the solution X-ray scattering of nanodiscs containing rhodopsin in the presence of rod arrestin to directly observe the formation of the rhodopsin/arrestin complex. Although arrestin self-associates to form a tetramer at physiological concentrations, it was found that arrestin binds to phosphorylated and photoactivated rhodopsin at 1:1 stoichiometry. In contrast, no complex formation was observed for unphosphorylated rhodopsin upon photoactivation, even at physiological arrestin concentrations, suggesting that the constitutive activity of rod arrestin is sufficiently low. UV-visible spectroscopy demonstrated that the rate of the formation of the rhodopsin/arrestin complex well correlates with the concentration of arrestin monomer rather than the tetramer. These findings indicate that arrestin monomer, whose concentration is almost constant due to the equilibrium with the tetramer, binds to phosphorylated rhodopsin. The arrestin tetramer would act as a reservoir of monomer to compensate for the large changes in arrestin concentration in rod cells caused by intense light or adaptation. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors in Cell Signaling Transduction)
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Article
Proximity Labeling to Identify β-Arrestin1 Binding Partners Downstream of Ligand-Activated G Protein-Coupled Receptors
Int. J. Mol. Sci. 2023, 24(4), 3285; https://doi.org/10.3390/ijms24043285 - 07 Feb 2023
Viewed by 985
Abstract
β-arrestins are multifaceted adaptor proteins that regulate various aspects of G protein-coupled receptor (GPCR) signaling. β-arrestins are recruited to agonist-activated and phosphorylated GPCRs at the plasma membrane, thereby preventing G protein coupling, while also targeting GPCRs for internalization via clathrin-coated pits. In addition, [...] Read more.
β-arrestins are multifaceted adaptor proteins that regulate various aspects of G protein-coupled receptor (GPCR) signaling. β-arrestins are recruited to agonist-activated and phosphorylated GPCRs at the plasma membrane, thereby preventing G protein coupling, while also targeting GPCRs for internalization via clathrin-coated pits. In addition, β-arrestins can activate various effector molecules to prosecute their role in GPCR signaling; however, the full extent of their interacting partners remains unknown. To discover potentially novel β-arrestin interacting partners, we used APEX-based proximity labeling coupled with affinity purification and quantitative mass spectrometry. We appended APEX in-frame to the C-terminus of β-arrestin1 (βarr1-APEX), which we show does not impact its ability to support agonist-stimulated internalization of GPCRs. By using coimmunoprecipitation, we show that βarr1-APEX interacts with known interacting proteins. Furthermore, following agonist stimulation βarr1-APEX labeled known βarr1-interacting partners as assessed by streptavidin affinity purification and immunoblotting. Aliquots were prepared in a similar manner and analyzed by tandem mass tag labeling and high-content quantitative mass spectrometry. Several proteins were found to be increased in abundance following GPCR stimulation. Biochemical experiments confirmed two novel proteins that interact with β-arrestin1, which we predict are novel ligand-stimulated βarr1 interacting partners. Our study highlights that βarr1-APEX-based proximity labeling represents a valuable approach to identifying novel players involved in GPCR signaling. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors in Cell Signaling Transduction)
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Review

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Review
Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands
Int. J. Mol. Sci. 2023, 24(7), 6187; https://doi.org/10.3390/ijms24076187 (registering DOI) - 24 Mar 2023
Viewed by 313
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors in Cell Signaling Transduction)
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Review
Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process
Int. J. Mol. Sci. 2022, 23(21), 13598; https://doi.org/10.3390/ijms232113598 - 06 Nov 2022
Cited by 1 | Viewed by 1178
Abstract
G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological process. They also constitute nearly 40% of the current pharmacopeia as direct targets of remedial [...] Read more.
G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological process. They also constitute nearly 40% of the current pharmacopeia as direct targets of remedial therapies. Hence, their place as a functional nexus in the interface between physiological and pathophysiological processes suggests that GPCRs may play a central role in the generation of nearly all types of human disease. Perhaps one mechanism through which GPCRs can mediate this pivotal function is through the control of the molecular aging process. It is now appreciated that, indeed, many human disorders/diseases are induced by GPCR signaling processes linked to pathological aging. Here we discuss one such novel member of the GPCR family, GPR19, that may represent an important new target for novel remedial strategies for the aging process. The molecular signaling pathways (metabolic control, circadian rhythm regulation and stress responsiveness) associated with this recently characterized receptor suggest an important role in aging-related disease etiology. Full article
(This article belongs to the Special Issue G Protein-Coupled Receptors in Cell Signaling Transduction)
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