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G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (10 April 2022) | Viewed by 31027

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Dr. Alessandro Cannavo

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Department of Translational Medical Sciences, University of Naples Federico II, 80138 Naples, Italy
Interests: cardiovascular disease; G protein coupled receptor; neurodegenerative disorders; periodontitis; pharmacology
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Over the past three decades, since Nobel prize winners Robert Lefkowitz and Brian Kobilka characterized the structure of G protein-coupled receptors (GPCRs), plenty of clinical and pharmacological evidence has advanced our knowledge around how these receptors, and their signaling pathways, influence almost every aspect of mammals’ physiology. Indeed, GPCRs can transduce cellular signals from neurohormones, sensory stimuli, and ions, and their activity is directly modulated by GPCR kinases (GRKs) by phosphorylation and subsequent desensitization. Nevertheless, an alteration in GRKs’ expression, with subsequent GPCR dysfunction, may induce, or at least influence, the development and progression of different systemic disorders. Thus, several drugs which are able to directly inhibit or enhance GPCR signaling have been developed and are currently used in clinical practice.

This Special Issue is calling for both original articles and reviews providing to the readers of IJMS a comprehensive elucidation of GPCR and GRK functions in cell biology necessary for developing novel research approaches as well as therapeutic strategies.

Dr. Alessandro Cannavo
Guest Editor

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Keywords

Cell biology
Cardiovascular disease
G protein-coupled receptor
GRK Ischemia
Neurodegeneration
Inflammation
Metabolism
Pharmacology

Published Papers (10 papers)

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Editorial

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3 pages, 195 KiB

Open AccessEditorial

Special Issue: “G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0”

by Alessandro Cannavo

Int. J. Mol. Sci. 2022, 23(23), 15152; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315152 - 02 Dec 2022

Viewed by 769

Abstract

The second volume of this Special Issue, entitled “G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2 [...] Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

Research

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14 pages, 1597 KiB

Open AccessArticle

GPR18-Mediated Relaxation of Human Isolated Pulmonary Arteries

by Hanna Kozłowska, Barbara Malinowska, Marta Baranowska-Kuczko, Magdalena Kusaczuk, Miłosz Nesterowicz, Mirosław Kozłowski, Christa E. Müller, Katarzyna Kieć-Kononowicz and Eberhard Schlicker

Int. J. Mol. Sci. 2022, 23(3), 1427; https://doi.org/10.3390/ijms23031427 - 26 Jan 2022

Cited by 7 | Viewed by 2773

Abstract

GPR18 receptor protein was detected in the heart and vasculature and appears to play a functional role in the cardiovascular system. We investigated the effects of the new GPR18 agonists PSB-MZ-1415 and PSB-MZ-1440 and the new GPR18 antagonist PSB-CB-27 on isolated human pulmonary arteries (hPAs) and compared their effects with the previously proposed, but unconfirmed, GPR18 ligands NAGly, Abn-CBD (agonists) and O-1918 (antagonist). GPR18 expression in hPAs was shown at the mRNA level. PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD fully relaxed endothelium-intact hPAs precontracted with the thromboxane A₂ analog U46619. PSB-CB-27 shifted the concentration-response curves (CRCs) of PSB-MZ-1415, PSB-MZ-1440, NAGly and Abn-CBD to the right; O-1918 caused rightward shifts of the CRCs of PSB-MZ-1415 and NAGly. Endothelium removal diminished the potency and the maximum effect of PSB-MZ-1415. The potency of PSB-MZ-1415 or NAGly was reduced in male patients, smokers and patients with hypercholesterolemia. In conclusion, the novel GPR18 agonists, PSB-MZ-1415 and PSB-MZ-1440, relax hPAs and the effect is inhibited by the new GPR18 antagonist PSB-CB-27. GPR18, which appears to exhibit lower activity in hPAs from male, smoking or hypercholesterolemic patients, may become a new target for the treatment of pulmonary arterial hypertension. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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16 pages, 3346 KiB

Open AccessArticle

Suitability of GRK Antibodies for Individual Detection and Quantification of GRK Isoforms in Western Blots

by Mona Reichel, Verena Weitzel, Laura Klement, Carsten Hoffmann and Julia Drube

Int. J. Mol. Sci. 2022, 23(3), 1195; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031195 - 21 Jan 2022

Cited by 5 | Viewed by 2352

Abstract

G protein-coupled receptors (GPCRs) are regulated by GPCR kinases (GRKs) which phosphorylate intracellular domains of the active receptor. This results in the recruitment of arrestins, leading to desensitization and internalization of the GPCR. Aside from acting on GPCRs, GRKs regulate a variety of membrane, cytosolic, and nuclear proteins not only via phosphorylation but also by acting as scaffolding partners. GRKs’ versatility is also reflected by their diverse roles in pathological conditions such as cancer, malaria, Parkinson’s-, cardiovascular-, and metabolic disease. Reliable tools to study GRKs are the key to specify their role in complex cellular signaling networks. Thus, we examined the specificity of eight commercially available antibodies targeting the four ubiquitously expressed GRKs (GRK2, GRK3, GRK5, and GRK6) in Western blot analysis. We identified one antibody that did not recognize its antigen, as well as antibodies that showed unspecific signals or cross-reactivity. Hence, we strongly recommend testing any antibody with exogenously expressed proteins to clearly confirm identity of the obtained Western blot results. Utilizing the most-suitable antibodies, we established the Western blot-based, cost-effective simple tag-guided analysis of relative protein abundance (STARPA). This method allows comparison of protein levels obtained by immunoblotting with different antibodies. Furthermore, we applied STARPA to determine GRK protein levels in nine commonly used cell lines, revealing differential isoform expression. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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20 pages, 3753 KiB

Open AccessArticle

ERα36–GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells

by George Notas, Athanasios Panagiotopoulos, Rodanthi Vamvoukaki, Konstantina Kalyvianaki, Foteini Kiagiadaki, Alexandra Deli, Marilena Kampa and Elias Castanas

Int. J. Mol. Sci. 2021, 22(14), 7603; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147603 - 16 Jul 2021

Cited by 10 | Viewed by 2316

Abstract

Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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10 pages, 2131 KiB

Open AccessArticle

Functional Characterization of the Obesity-Linked Variant of the β₃-Adrenergic Receptor

by Esraa Haji, Saeed Al Mahri, Yumna Aloraij, Shuja Shafi Malik and Sameer Mohammad

Int. J. Mol. Sci. 2021, 22(11), 5721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115721 - 27 May 2021

Cited by 6 | Viewed by 2731

Abstract

Adrenergic receptor β₃ (ADRβ₃) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of the ligand to ADRβ₃ activates adenylate cyclase and increases cAMP in the cells. ADRβ₃ is highly expressed in white and brown adipocytes and controls key regulatory pathways of lipid metabolism. Trp64Arg (W64R) polymorphism in the ADRβ₃ is associated with the early development of type 2 diabetes mellitus, lower resting metabolic rate, abdominal obesity, and insulin resistance. It is unclear how the substitution of W64R affects the functioning of ADRβ₃. This study was initiated to functionally characterize this obesity-linked variant of ADRβ₃. We evaluated in detail the expression, subcellular distribution, and post-activation behavior of the WT and W64R ADRβ₃ using single cell quantitative fluorescence microscopy. When expressed in HEK 293 cells, ADRβ₃ shows a typical distribution displayed by other GPCRs with a predominant localization at the cell surface. Unlike adrenergic receptor β₂ (ADRβ₂), agonist-induced desensitization of ADRβ₃ does not involve loss of cell surface expression. WT and W64R variant of ADRβ₃ displayed comparable biochemical properties, and there was no significant impact of the substitution of tryptophan with arginine on the expression, cellular distribution, signaling, and post-activation behavior of ADRβ₃. The obesity-linked W64R variant of ADRβ₃ is indistinguishable from the WT ADRβ₃ in terms of expression, cellular distribution, signaling, and post-activation behavior. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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24 pages, 4394 KiB

Open AccessArticle

Deregulation of Ca²⁺-Signaling Systems in White Adipocytes, Manifested as the Loss of Rhythmic Activity, Underlies the Development of Multiple Hormonal Resistance at Obesity and Type 2 Diabetes

by Egor A. Turovsky, Maria V. Turovskaya and Vladimir V. Dynnik

Int. J. Mol. Sci. 2021, 22(10), 5109; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105109 - 12 May 2021

Cited by 7 | Viewed by 2185

Abstract

Various types of cells demonstrate ubiquitous rhythmicity registered as simple and complex Ca²⁺-oscillations, spikes, waves, and triggering phenomena mediated by G-protein and tyrosine kinase coupled receptors. Phospholipase C/IP₃-receptors (PLC/IP₃R) and endothelial NO-synthase/Ryanodine receptors (NOS/RyR)–dependent Ca²⁺ signaling systems, organized as multivariate positive feedback generators (PLC-G and NOS-G), underlie this rhythmicity. Loss of rhythmicity at obesity may indicate deregulation of these signaling systems. To issue the impact of cell size, receptors’ interplay, and obesity on the regulation of PLC-G and NOS-G, we applied fluorescent microscopy, immunochemical staining, and inhibitory analysis using cultured adipocytes of epididumal white adipose tissue of mice. Acetylcholine, norepinephrine, atrial natriuretic peptide, bradykinin, cholecystokinin, angiotensin II, and insulin evoked complex [Ca²⁺]_i responses in adipocytes, implicating NOS-G or PLC-G. At low sub-threshold concentrations, acetylcholine and norepinephrine or acetylcholine and peptide hormones (in paired combinations) recruited NOS-G, based on G proteins subunits interplay and signaling amplification. Rhythmicity was cell size- dependent and disappeared in hypertrophied cells filled with lipids. Contrary to control cells, adipocytes of obese hyperglycemic and hypertensive mice, growing on glucose, did not accumulate lipids and demonstrated hormonal resistance being non responsive to any hormone applied. Preincubation of preadipocytes with palmitoyl-L-carnitine (100 nM) provided accumulation of lipids, increased expression and clustering of IP₃R and RyR proteins, and partially restored hormonal sensitivity and rhythmicity (5–15% vs. 30–80% in control cells), while adipocytes of diabetic mice were not responsive at all. Here, we presented a detailed kinetic model of NOS-G and discussed its control. Collectively, we may suggest that universal mechanisms underlie loss of rhythmicity, Ca²⁺-signaling systems deregulation, and development of general hormonal resistance to obesity. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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Review

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19 pages, 738 KiB

Open AccessReview

Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate

by Beatrice Arosio, Graziamaria Corbi, Sergio Davinelli, Vienna Giordano, Daniela Liccardo, Antonio Rapacciuolo and Alessandro Cannavo

Int. J. Mol. Sci. 2022, 23(7), 4009; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23074009 - 04 Apr 2022

Cited by 13 | Viewed by 2958

Abstract

The medical community recognizes sex-related differences in pathophysiology and cardiovascular disease outcomes (CVD), culminating with heart failure. In general, pre-menopausal women tend to have a better prognosis than men. Explaining why this occurs is not a simple matter. For decades, sex hormones like estrogens (Es) have been identified as one of the leading factors driving these sex differences. Indeed, Es seem protective in women as their decline, during and after menopause, coincides with an increased CV risk and HF development. However, clinical trials demonstrated that E replacement in post-menopause women results in adverse cardiac events and increased risk of breast cancer. Thus, a deeper understanding of E-related mechanisms is needed to provide a vital gateway toward better CVD prevention and treatment in women. Of note, sphingolipids (SLs) and their metabolism are strictly related to E activities. Among the SLs, ceramide and sphingosine 1-phosphate play essential roles in mammalian physiology, particularly in the CV system, and appear differently modulated in males and females. In keeping with this view, here we explore the most recent experimental and clinical observations about the role of E and SL metabolism, emphasizing how these factors impact the CV system. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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36 pages, 1239 KiB

Open AccessReview

Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease

by Georgi Nikolaev, Ralitsa Robeva and Rossitza Konakchieva

Int. J. Mol. Sci. 2022, 23(1), 471; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010471 - 31 Dec 2021

Cited by 28 | Viewed by 5506

Abstract

The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology—for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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18 pages, 2849 KiB

Open AccessReview

The LPA₃ Receptor: Regulation and Activation of Signaling Pathways

by Karina Helivier Solís, M. Teresa Romero-Ávila, Alejandro Guzmán-Silva and J. Adolfo García-Sáinz

Int. J. Mol. Sci. 2021, 22(13), 6704; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136704 - 23 Jun 2021

Cited by 6 | Viewed by 3856

Abstract

The lysophosphatidic acid 3 receptor (LPA₃) participates in different physiological actions and in the pathogenesis of many diseases through the activation of different signal pathways. Knowledge of the regulation of the function of the LPA₃ receptor is a crucial element for defining its roles in health and disease. This review describes what is known about the signaling pathways activated in terms of its various actions. Next, we review knowledge on the structure of the LPA₃ receptor, the domains found, and the roles that the latter might play in ligand recognition, signaling, and cellular localization. Currently, there is some information on the action of LPA₃ in different cells and whole organisms, but very little is known about the regulation of its function. Areas in which there is a gap in our knowledge are indicated in order to further stimulate experimental work on this receptor and on other members of the LPA receptor family. We are convinced that knowledge on how this receptor is activated, the signaling pathways employed and how the receptor internalization and desensitization are controlled will help design new therapeutic interventions for treating diseases in which the LPA₃ receptor is implicated. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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13 pages, 1131 KiB

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New Structural Perspectives in G Protein-Coupled Receptor-Mediated Src Family Kinase Activation

by Sandra Berndt and Ines Liebscher

Int. J. Mol. Sci. 2021, 22(12), 6489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126489 - 17 Jun 2021

Cited by 13 | Viewed by 4276

Abstract

Src family kinases (SFKs) are key regulators of cell proliferation, differentiation, and survival. The expression of these non-receptor tyrosine kinases is strongly correlated with cancer development and tumor progression. Thus, this family of proteins serves as an attractive drug target. The activation of SFKs can occur via multiple signaling pathways, yet many of them are poorly understood. Here, we summarize the current knowledge on G protein-coupled receptor (GPCR)-mediated regulation of SFKs, which is of considerable interest because GPCRs are among the most widely used pharmaceutical targets. This type of activation can occur through a direct interaction between the two proteins or be allosterically regulated by arrestins and G proteins. We postulate that a rearrangement of binding motifs within the active conformation of arrestin-3 mediates Src regulation by comparison of available crystal structures. Therefore, we hypothesize a potentially different activation mechanism compared to arrestin-2. Furthermore, we discuss the probable direct regulation of SFK by GPCRs and investigate the intracellular domains of exemplary GPCRs with conserved polyproline binding motifs that might serve as scaffolding domains to allow such a direct interaction. Large intracellular domains in GPCRs are often understudied and, in general, not much is known of their contribution to different signaling pathways. The suggested direct interaction between a GPCR and a SFK could allow for a potential immediate allosteric regulation of SFKs by GPCRs and thereby unravel a novel mechanism of SFK signaling. This overview will help to identify new GPCR–SFK interactions, which could serve to explain biological functions or be used to modulate downstream effectors. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0)

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