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Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 February 2021) | Viewed by 39690

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Special Issue Editors

Prof. Federico Mayor

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Guest Editor

Departamento de Biología Molecular Centro de BiologíaMolecular "Severo Ochoa" c/ Nicolás Cabrera, 1 Universidad Autónoma de Madrid, 28049 Madrid, Spain

Prof. Cristina Murga

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Guest Editor

Departamento de Biología Molecular Centro de BiologíaMolecular "Severo Ochoa" c/ Nicolás Cabrera, 1 Universidad Autónoma de Madrid, 28049 Madrid, Spain

Special Issue Information

Dear Colleagues,

G protein-coupled receptor kinases (GRKs) constitute a family of seven serine/threonine protein kinases that specifically phosphorylate agonist-activated G protein-coupled receptors (GPCRs), thus priming the association of b-arrestins that prompt uncoupling from G proteins, GPCR trafficking, and alternative signaling pathways. Moreover, GRKs are emerging as signal transducers by themselves, being able to interact with (and in many cases phosphorylate) a variety of non-GPCR proteins. Consistent with such complex interactomes, GRKs are increasingly being reported to participate in important cellular and physiological processes central to very prevalent human pathologies, such as cancer, cardiovascular, metabolic, and neurological disorders, among others. Moreover, changes in the levels or functionality of specific GRKs correlate with disease onset or progression in different pathological contexts. Therefore, GRKs are being increasingly regarded as potential diagnostic or therapeutic targets.

This Special Issue will feature both original articles and reviews providing the readers of Cells with a comprehensive approach to the more innovative insights of the cellular and molecular biology of GRKs and their relationship with potential therapeutic strategies based on these multifunctional molecules.

Prof. Federico Mayor
Prof. Cristina Murga
Guest Editors

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (12 papers)

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Editorial

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3 pages, 216 KiB

Open AccessEditorial

G Protein-Coupled Receptor Kinases Take Central Stage

by Federico Mayor, Jr. and Cristina Murga

Cells 2023, 12(1), 23; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12010023 - 21 Dec 2022

Cited by 3 | Viewed by 891

Abstract

The relevance of the family of G protein-coupled receptor kinases (GRKs) is based on its key participation in the regulation and intracellular dynamics of the largest family of membrane receptors, namely G protein-coupled receptors (GPCRs) [...] Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

Research

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20 pages, 4559 KiB

Open AccessArticle

Mdm2-Mediated Downmodulation of GRK2 Restricts Centrosome Separation for Proper Chromosome Congression

by Clara Reglero, Belén Ortiz del Castillo, Verónica Rivas, Federico Mayor, Jr. and Petronila Penela

Cells 2021, 10(4), 729; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040729 - 25 Mar 2021

Cited by 2 | Viewed by 2314

Abstract

The timing of centrosome separation and the distance moved apart influence the formation of the bipolar spindle, affecting chromosome stability. Epidermal growth factor receptor (EGFR) signaling induces early centrosome separation through downstream G protein-coupled receptor kinase GRK2, which phosphorylates the Hippo pathway component MST2 (Mammalian STE20-like protein kinase 2), in turn allowing NIMA kinase Nek2A activation for centrosomal linker disassembly. However, the mechanisms that counterbalance centrosome disjunction and separation remain poorly understood. We unveil that timely degradation of GRK2 by the E3 ligase Mdm2 limits centrosome separation in the G2. Both knockout expression and catalytic inhibition of Mdm2 result in GRK2 accumulation and enhanced centrosome separation before mitosis onset. Phosphorylation of GRK2 on residue S670 enables a complex pattern of non-K48-linked polyubiquitin chains assembled by Mdm2, which correlate with kinase protein degradation. Remarkably, GRK2-S670A protein fails to phosphorylate MST2 despite overcoming Mdm2-dependent degradation, which results in defective centrosome separation, shorter spindles, and abnormal chromosome congression. Conversely, extra levels of wild-type kinase in the G2 cause increased inter-centrosome distances with longer spindles, also converging in congression issues. Our findings show that the signals enabling activity of the GRK2/MST2/Nek2A axis for separation also switches on Mdm2 degradation of GRK2 to ensure accurate centrosome dynamics and proper mitotic spindle functionality. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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14 pages, 2043 KiB

Open AccessArticle

Cardiac GRK2 Protein Levels Show Sexual Dimorphism during Aging and Are Regulated by Ovarian Hormones

by Alba C. Arcones, Melanie Raquel Martínez-Cignoni, Rocío Vila-Bedmar, Claudia Yáñez, Isabel Lladó, Ana M. Proenza, Federico Mayor, Jr. and Cristina Murga

Cells 2021, 10(3), 673; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030673 - 17 Mar 2021

Cited by 8 | Viewed by 2427

Abstract

Cardiovascular disease (CVD) risk shows a clear sexual dimorphism with age, with a lower incidence in young women compared to age-matched men. However, this protection is lost after menopause. We demonstrate that sex-biased sensitivity to the development of CVD with age runs in parallel with changes in G protein-coupled receptor kinase 2 (GRK2) protein levels in the murine heart and that mitochondrial fusion markers, related to mitochondrial functionality and cardiac health, inversely correlate with GRK2. Young female mice display lower amounts of cardiac GRK2 protein compared to age-matched males, whereas GRK2 is upregulated with age specifically in female hearts. Such an increase in GRK2 seems to be specific to the cardiac muscle since a different pattern is found in the skeletal muscles of aging females. Changes in the cardiac GRK2 protein do not seem to rely on transcriptional modulation since adrbk1 mRNA does not change with age and no differences are found between sexes. Global changes in proteasomal or autophagic machinery (known regulators of GRK2 dosage) do not seem to correlate with the observed GRK2 dynamics. Interestingly, cardiac GRK2 upregulation in aging females is recapitulated by ovariectomy and can be partially reversed by estrogen supplementation, while this does not occur in the skeletal muscle. Our data indicate an unforeseen role for ovarian hormones in the regulation of GRK2 protein levels in the cardiac muscle which correlates with the sex-dependent dynamics of CVD risk, and might have interesting therapeutic applications, particularly for post-menopausal women. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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16 pages, 4196 KiB

Open AccessArticle

Differential Involvement of ACKR3 C-Tail in β-Arrestin Recruitment, Trafficking and Internalization

by Aurélien Zarca, Claudia Perez, Jelle van den Bor, Jan Paul Bebelman, Joyce Heuninck, Rianna J. F. de Jonker, Thierry Durroux, Henry F. Vischer, Marco Siderius and Martine J. Smit

Cells 2021, 10(3), 618; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030618 - 11 Mar 2021

Cited by 20 | Viewed by 5204

Abstract

Background: The atypical chemokine receptor 3 (ACKR3) belongs to the superfamily of G protein-coupled receptors (GPCRs). Unlike classical GPCRs, this receptor does not activate G proteins in most cell types but recruits β-arrestins upon activation. ACKR3 plays an important role in cancer and vascular diseases. As recruitment of β-arrestins is triggered by phosphorylation of the C-terminal tail of GPCRs, we studied the role of different potential phosphorylation sites within the ACKR3 C-tail to further delineate the molecular mechanism of internalization and trafficking of this GPCR. Methods: We used various bioluminescence and fluorescence resonance energy transfer-based sensors and techniques in Human Embryonic Kidney (HEK) 293T cells expressing WT or phosphorylation site mutants of ACKR3 to measure CXCL12-induced recruitment of β-arrestins and G-protein-coupled receptor kinases (GRKs), receptor internalization and trafficking. Results: Upon CXCL12 stimulation, ACKR3 recruits both β-arrestin 1 and 2 with equivalent kinetic profiles. We identified interactions with GRK2, 3 and 5, with GRK2 and 3 being important for β-arrestin recruitment. Upon activation, ACKR3 internalizes and recycles back to the cell membrane. We demonstrate that β-arrestin recruitment to the receptor is mainly determined by a single cluster of phosphorylated residues on the C-tail of ACKR3, and that residue T³⁵² and in part S³⁵⁵ are important residues for β-arrestin1 recruitment. Phosphorylation of the C-tail appears essential for ligand-induced internalization and important for differential β-arrestin recruitment. GRK2 and 3 play a key role in receptor internalization. Moreover, ACKR3 can still internalize when β-arrestin recruitment is impaired or in the absence of β-arrestins, using alternative internalization pathways. Our data indicate that distinct residues within the C-tail of ACKR3 differentially regulate CXCL12-induced β-arrestin recruitment, ACKR3 trafficking and internalization. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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Review

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10 pages, 1131 KiB

Open AccessReview

Historical Perspective of the G Protein-Coupled Receptor Kinase Family

by Jeffrey L. Benovic

Cells 2021, 10(3), 555; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030555 - 04 Mar 2021

Cited by 18 | Viewed by 2622

Abstract

Agonist activation of G protein-coupled receptors promotes sequential interaction of the receptor with heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs), and arrestins. GRKs play a central role in mediating the switch from G protein to arrestin interaction and thereby control processes such as receptor desensitization and trafficking and arrestin-mediated signaling. In this review, I provide a historical perspective on some of the early studies that identified the family of GRKs with a primary focus on the non-visual GRKs. These studies included identification, purification, and cloning of the β-adrenergic receptor kinase in the mid- to late-1980s and subsequent cloning and characterization of additional members of the GRK family. This helped to lay the groundwork for ensuing work focused on understanding the structure and function of these important enzymes. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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16 pages, 814 KiB

Open AccessReview

Why Do We Not Assess Sympathetic Nervous System Activity in Heart Failure Management: Might GRK2 Serve as a New Biomarker?

by Leonardo Bencivenga, Maria Emiliana Palaia, Immacolata Sepe, Giuseppina Gambino, Klara Komici, Alessandro Cannavo, Grazia Daniela Femminella and Giuseppe Rengo

Cells 2021, 10(2), 457; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020457 - 21 Feb 2021

Cited by 14 | Viewed by 2966

Abstract

Heart failure (HF) represents the end-stage condition of several structural and functional cardiovascular diseases, characterized by reduced myocardial pump function and increased pressure load. The dysregulation of neurohormonal systems, especially the hyperactivity of the cardiac adrenergic nervous system (ANS), constitutes a hallmark of HF and exerts a pivotal role in its progression. Indeed, it negatively affects patients’ prognosis, being associated with high morbidity and mortality rates, with a tremendous burden on global healthcare systems. To date, all the techniques proposed to assess the cardiac sympathetic nervous system are burdened by intrinsic limits that hinder their implementation in clinical practice. Several biomarkers related to ANS activity, which may potentially support the clinical management of such a complex syndrome, are slow to be implemented in the routine practice for several limitations due to their assessment and clinical impact. Lymphocyte G-protein-coupled Receptor Kinase 2 (GRK2) levels reflect myocardial β-adrenergic receptor function in HF and have been shown to add independent prognostic information related to ANS overdrive. In the present manuscript, we provide an overview of the techniques currently available to evaluate cardiac ANS in HF and future perspectives in this field of relevant scientific and clinical interest. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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13 pages, 822 KiB

Open AccessReview

Canonical and Non-Canonical Roles of GRK2 in Lymphocytes

by Jing Cheng, Peter C. Lucas and Linda M. McAllister-Lucas

Cells 2021, 10(2), 307; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020307 - 03 Feb 2021

Cited by 8 | Viewed by 3585

Abstract

G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2′s canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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15 pages, 1687 KiB

Open AccessReview

The Metabolic Role of GRK2 in Insulin Resistance and Associated Conditions

by Daniela Sorriento, Maria Rosaria Rusciano, Valeria Visco, Antonella Fiordelisi, Federica Andrea Cerasuolo, Paolo Poggio, Michele Ciccarelli and Guido Iaccarino

Cells 2021, 10(1), 167; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010167 - 15 Jan 2021

Cited by 13 | Viewed by 3613

Abstract

Insulin resistance (IRES) is a pathophysiological condition characterized by the reduced response to insulin of several tissues, including myocardial and skeletal muscle. IRES is associated with obesity, glucose intolerance, dyslipidemia, and hypertension, evolves toward type 2 diabetes, and increases the risk of developing cardiovascular diseases. Several studies designed to explore the mechanisms involved in IRES allowed the identification of a multitude of potential molecular targets. Among the most promising, G Protein Coupled Receptor Kinase type 2 (GRK2) appears to be a suitable one given its functional implications in many cellular processes. In this review, we will discuss the metabolic role of GRK2 in those conditions that are characterized by insulin resistance (diabetes, hypertension, heart failure), and the potentiality of its inhibition as a therapeutic strategy to revert both insulin resistance and its associated phenotypes. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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17 pages, 2227 KiB

Open AccessReview

GRKs and Epac1 Interaction in Cardiac Remodeling and Heart Failure

by Marion Laudette, Karina Formoso and Frank Lezoualc’h

Cells 2021, 10(1), 154; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010154 - 14 Jan 2021

Cited by 6 | Viewed by 3119

Abstract

β-adrenergic receptors (β-ARs) play a major role in the physiological regulation of cardiac function through signaling routes tightly controlled by G protein-coupled receptor kinases (GRKs). Although the acute stimulation of β-ARs and the subsequent production of cyclic AMP (cAMP) have beneficial effects on cardiac function, chronic stimulation of β-ARs as observed under sympathetic overdrive promotes the development of pathological cardiac remodeling and heart failure (HF), a leading cause of mortality worldwide. This is accompanied by an alteration in cAMP compartmentalization and the activation of the exchange protein directly activated by cAMP 1 (Epac1) signaling. Among downstream signals of β-ARs, compelling evidence indicates that GRK2, GRK5, and Epac1 represent attractive therapeutic targets for cardiac disease. Here, we summarize the pathophysiological roles of GRK2, GRK5, and Epac1 in the heart. We focus on their signalosome and describe how under pathological settings, these proteins can cross-talk and are part of scaffolded nodal signaling systems that contribute to a decreased cardiac function and HF development. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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21 pages, 16395 KiB

Open AccessReview

The G Protein-Coupled Receptor Kinases (GRKs) in Chemokine Receptor-Mediated Immune Cell Migration: From Molecular Cues to Physiopathology

by Marta Laganà, Géraldine Schlecht-Louf and Françoise Bachelerie

Cells 2021, 10(1), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010075 - 05 Jan 2021

Cited by 12 | Viewed by 4072

Abstract

Although G protein-coupled receptor kinases (GRKs) have long been known to regulate G protein-coupled receptor (GPCR) desensitization, their more recently characterized functions as scaffolds and signalling adapters underscore that this small family of proteins governs a larger array of physiological functions than originally suspected. This review explores how GRKs contribute to the complex signalling networks involved in the migration of immune cells along chemokine gradients sensed by cell surface GPCRs. We outline emerging evidence indicating that the coordinated docking of several GRKs on an active chemokine receptor determines a specific receptor phosphorylation barcode that will translate into distinct signalling and migration outcomes. The guidance cues for neutrophil migration are emphasized based on several alterations affecting GRKs or GPCRs reported to be involved in pathological conditions. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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Graphical abstract

27 pages, 2027 KiB

Open AccessReview

GRKs as Modulators of Neurotransmitter Receptors

by Eugenia V. Gurevich and Vsevolod V. Gurevich

Cells 2021, 10(1), 52; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010052 - 31 Dec 2020

Cited by 14 | Viewed by 3974

Abstract

Many receptors for neurotransmitters, such as dopamine, norepinephrine, acetylcholine, and neuropeptides, belong to the superfamily of G protein-coupled receptors (GPCRs). A general model posits that GPCRs undergo two-step homologous desensitization: the active receptor is phosphorylated by kinases of the G protein-coupled receptor kinase (GRK) family, whereupon arrestin proteins specifically bind active phosphorylated receptors, shutting down G protein-mediated signaling, facilitating receptor internalization, and initiating distinct signaling pathways via arrestin-based scaffolding. Here, we review the mechanisms of GRK-dependent regulation of neurotransmitter receptors, focusing on the diverse modes of GRK-mediated phosphorylation of receptor subtypes. The immediate signaling consequences of GRK-mediated receptor phosphorylation, such as arrestin recruitment, desensitization, and internalization/resensitization, are equally diverse, depending not only on the receptor subtype but also on phosphorylation by GRKs of select receptor residues. We discuss the signaling outcome as well as the biological and behavioral consequences of the GRK-dependent phosphorylation of neurotransmitter receptors where known. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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15 pages, 971 KiB

Open AccessReview

GRKs as Key Modulators of Opioid Receptor Function

by Laura Lemel, J Robert Lane and Meritxell Canals

Cells 2020, 9(11), 2400; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112400 - 02 Nov 2020

Cited by 10 | Viewed by 3961

Abstract

Understanding the link between agonist-induced phosphorylation of the mu-opioid receptor (MOR) and the associated physiological effects is critical for the development of novel analgesic drugs and is particularly important for understanding the mechanisms responsible for opioid-induced tolerance and addiction. The family of G protein receptor kinases (GRKs) play a pivotal role in such processes, mediating phosphorylation of residues at the C-tail of opioid receptors. Numerous strategies, such as phosphosite specific antibodies and mass spectrometry have allowed the detection of phosphorylated residues and the use of mutant knock-in mice have shed light on the role of GRK regulation in opioid receptor physiology. Here we review our current understanding on the role of GRKs in the actions of opioid receptors, with a particular focus on the MOR, the target of most commonly used opioid analgesics such as morphine or fentanyl. Full article

(This article belongs to the Special Issue Novel Insights on G Protein-Coupled Receptor Kinases: From Cell Biology to Pathology)

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