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GPCR Structure and Function in Disease
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GPCR Structure and Function in Disease

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 (31 December 2018) | Viewed by 58570

Special Issue Editors

Prof. Dr. Yingzi Cong

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Guest Editor
Department of Microbiology and Immunology, UT Medical Branch at Galveston, Galveston, TX, USA
Interests: GPCR; microbiota; intestines; IBD; mucosal immunology
Prof. Dr. Zhanju Liu

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Guest Editor
Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
Interests: IBD; mucosal immunology; GPCR; T cells, epithelial cells, microbiota

Special Issue Information

Dear Colleagues

G protein-coupled receptors (GPCRs) are expressed by various types of cells and recognize an array of various stimuli from both hosts and environments. These receptors modulate the key pathways in various systems and participate in many different cellular processes, which are involved in regulation of human diseases. Thus, GPCRs are potential therapeutic targets for a range of diseases.  

The research topics in this Special Issue focus on the roles of GPCRs in various diseases, both in human patients and in experimental disease models. The scope of these topics include, but are not limited to, the mechanisms underlying GPCR signaling in regulation of pathogenesis of diseases; GPCRs and their downstream signaling pathways in disease; modulation of diseases by GPCRs; and host responses to potential therapeutic strategies targeting GPCRs.

Prof. Dr. Yingzi Cong
Prof. Dr. Zhanju Liu
Guest Editors

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Keywords

  • G protein-coupled receptors
  • autoimmune diseases
  • inflammatory diseases
  • microbiota
  • diets

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Published Papers (7 papers)

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Research

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14 pages, 1905 KiB  
Article
Role of the G-Protein-Coupled Receptor Signaling Pathway in Insecticide Resistance
by Ting Li and Nannan Liu
Int. J. Mol. Sci. 2019, 20(17), 4300; https://doi.org/10.3390/ijms20174300 - 3 Sep 2019
Cited by 25 | Viewed by 4145
Abstract
The G-protein-coupled receptor (GPCR) regulated intracellular signaling pathway is known to be involved in the development of insecticide resistance in the mosquito, Culex quinquefasciatus. To elucidate the specific role of each effector in the GPCR regulating pathway, we initially expressed a GPCR, [...] Read more.
The G-protein-coupled receptor (GPCR) regulated intracellular signaling pathway is known to be involved in the development of insecticide resistance in the mosquito, Culex quinquefasciatus. To elucidate the specific role of each effector in the GPCR regulating pathway, we initially expressed a GPCR, G-protein alpha subunit (Gαs), adenylate cyclase (AC), and protein kinase A (PKA) in insect Spodoptera frugiperda (Sf9) cells and investigated their regulation function on cyclic AMP (cAMP) production and PKA activity. GPCR, Gαs, and AC individually expressed Sf9 cells showed higher cAMP production as the expression of each effector increased. All the effector-expressed cell lines showed increased PKA activity however. Moreover, Sf9 cytochrome P450 gene expression and cell tolerance to permethrin were examined. The relative expression of CYP9A32gene in Sf9 cells tested was significantly increased in all effector-expressed cell lines compared to a control cell line; these effector-expressed cell lines also showed significantly higher tolerance to permethrin. Inhibitor treatments on each effector-expressed cell line revealed that Bupivacaine HCl and H89 2HCl robustly inhibited cAMP production and PKA activity, respectively, resulting in decreased tolerance to permethrin in all cell lines. The synergistic functions of Bupivacaine HCl and H89 2HCl with permethrin were further examined in Culex mosquito larvae, providing a valuable new information for mosquito control strategies. Full article
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
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25 pages, 3064 KiB  
Article
Distinct Dopamine D2 Receptor Antagonists Differentially Impact D2 Receptor Oligomerization
by Elise Wouters, Adrián Ricarte Marín, James Andrew Rupert Dalton, Jesús Giraldo and Christophe Stove
Int. J. Mol. Sci. 2019, 20(7), 1686; https://doi.org/10.3390/ijms20071686 - 4 Apr 2019
Cited by 26 | Viewed by 6175
Abstract
Dopamine D2 receptors (D2R) are known to form transient homodimer complexes, of which the increased formation has already been associated with development of schizophrenia. Pharmacological targeting and modulation of the equilibrium of these receptor homodimers might lead to a better [...] Read more.
Dopamine D2 receptors (D2R) are known to form transient homodimer complexes, of which the increased formation has already been associated with development of schizophrenia. Pharmacological targeting and modulation of the equilibrium of these receptor homodimers might lead to a better understanding of the critical role played by these complexes in physiological and pathological conditions. Whereas agonist addition has shown to prolong the D2R dimer lifetime and increase the level of dimer formation, the possible influence of D2R antagonists on dimerization has remained rather unexplored. Here, using a live-cell reporter assay based on the functional complementation of a split Nanoluciferase, a panel of six D2R antagonists were screened for their ability to modulate the level of D2LR dimer formation. Incubation with the D2R antagonist spiperone decreased the level of D2LR dimer formation significantly by 40–60% in real-time and after long-term (≥16 h) incubations. The fact that dimer formation of the well-studied A2a–D2LR dimer was not altered following incubation with spiperone supports the specificity of this observation. Other D2R antagonists, such as clozapine, risperidone, and droperidol did not significantly evoke this dissociation event. Furthermore, molecular modeling reveals that spiperone presents specific Tyr1995.48 and Phe3906.52 conformations, compared to clozapine, which may determine D2R homodimerization. Full article
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
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Review

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18 pages, 1023 KiB  
Review
Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders
by Hidetoshi Komatsu, Mamoru Fukuchi and Yugo Habata
Int. J. Mol. Sci. 2019, 20(13), 3207; https://doi.org/10.3390/ijms20133207 - 29 Jun 2019
Cited by 24 | Viewed by 12489
Abstract
Tremendous advances have been made recently in the identification of genes and signaling pathways associated with the risks for psychiatric disorders such as schizophrenia and bipolar disorder. However, there has been a marked reduction in the pipeline for the development of new psychiatric [...] Read more.
Tremendous advances have been made recently in the identification of genes and signaling pathways associated with the risks for psychiatric disorders such as schizophrenia and bipolar disorder. However, there has been a marked reduction in the pipeline for the development of new psychiatric drugs worldwide, mainly due to the complex causes that underlie these disorders. G-protein coupled receptors (GPCRs) are the most common targets of antipsychotics such as quetiapine and aripiprazole, and play pivotal roles in controlling brain function by regulating multiple downstream signaling pathways. Progress in our understanding of GPCR signaling has opened new possibilities for selective drug development. A key finding has been provided by the concept of biased ligands, which modulate some, but not all, of a given receptor’s downstream signaling pathways. Application of this concept raises the possibility that the biased ligands can provide therapeutically desirable outcomes with fewer side effects. Instead, this application will require a detailed understanding of the mode of action of antipsychotics that drive distinct pharmacologies. We review our current understanding of the mechanistic bases for multiple signaling modes by antipsychotics and the potential of the biased modulators to treat mental disorders. Full article
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
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35 pages, 2256 KiB  
Review
Luminescence- and Fluorescence-Based Complementation Assays to Screen for GPCR Oligomerization: Current State of the Art
by Elise Wouters, Lakshmi Vasudevan, René A. J. Crans, Deepak K. Saini and Christophe P. Stove
Int. J. Mol. Sci. 2019, 20(12), 2958; https://doi.org/10.3390/ijms20122958 - 17 Jun 2019
Cited by 31 | Viewed by 8558
Abstract
G protein-coupled receptors (GPCRs) have the propensity to form homo- and heterodimers. Dysfunction of these dimers has been associated with multiple diseases, e.g., pre-eclampsia, schizophrenia, and depression, among others. Over the past two decades, considerable efforts have been made towards the development of [...] Read more.
G protein-coupled receptors (GPCRs) have the propensity to form homo- and heterodimers. Dysfunction of these dimers has been associated with multiple diseases, e.g., pre-eclampsia, schizophrenia, and depression, among others. Over the past two decades, considerable efforts have been made towards the development of screening assays for studying these GPCR dimer complexes in living cells. As a first step, a robust in vitro assay in an overexpression system is essential to identify and characterize specific GPCR–GPCR interactions, followed by methodologies to demonstrate association at endogenous levels and eventually in vivo. This review focuses on protein complementation assays (PCAs) which have been utilized to study GPCR oligomerization. These approaches are typically fluorescence- and luminescence-based, making identification and localization of protein–protein interactions feasible. The GPCRs of interest are fused to complementary fluorescent or luminescent fragments that, upon GPCR di- or oligomerization, may reconstitute to a functional reporter, of which the activity can be measured. Various protein complementation assays have the disadvantage that the interaction between the reconstituted split fragments is irreversible, which can lead to false positive read-outs. Reversible systems offer several advantages, as they do not only allow to follow the kinetics of GPCR–GPCR interactions, but also allow evaluation of receptor complex modulation by ligands (either agonists or antagonists). Protein complementation assays may be used for high throughput screenings as well, which is highly relevant given the growing interest and effort to identify small molecule drugs that could potentially target disease-relevant dimers. In addition to providing an overview on how PCAs have allowed to gain better insights into GPCR–GPCR interactions, this review also aims at providing practical guidance on how to perform PCA-based assays. Full article
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
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24 pages, 2812 KiB  
Review
Structural Insights into CB1 Receptor Biased Signaling
by Rufaida Al-Zoubi, Paula Morales and Patricia H. Reggio
Int. J. Mol. Sci. 2019, 20(8), 1837; https://doi.org/10.3390/ijms20081837 - 13 Apr 2019
Cited by 61 | Viewed by 9955
Abstract
The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) [...] Read more.
The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling. Full article
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
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21 pages, 2123 KiB  
Review
Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors
by Antonella Di Pizio, Maik Behrens and Dietmar Krautwurst
Int. J. Mol. Sci. 2019, 20(6), 1402; https://doi.org/10.3390/ijms20061402 - 20 Mar 2019
Cited by 59 | Viewed by 8576
Abstract
G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). [...] Read more.
G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). Interestingly, these chemosensory GPCRs (csGPCRs) are expressed in several tissues of the body where they are supposed to play a role in biological functions other than chemosensation. Despite their abundance and physiological/pathological relevance, the druggability of csGPCRs has been suggested but not fully characterized. Here, we aim to explore the potential of targeting csGPCRs to treat diseases by reviewing the current knowledge of csGPCRs expressed throughout the body and by analysing the chemical space and the drug-likeness of flavour molecules. Full article
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
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20 pages, 1041 KiB  
Review
Revisiting the Cardioprotective Effects of Acetylcholine Receptor Activation against Myocardial Ischemia/Reperfusion Injury
by Kannaporn Intachai, Siriporn C. Chattipakorn, Nipon Chattipakorn and Krekwit Shinlapawittayatorn
Int. J. Mol. Sci. 2018, 19(9), 2466; https://doi.org/10.3390/ijms19092466 - 21 Aug 2018
Cited by 47 | Viewed by 7680
Abstract
Acute myocardial infarction (AMI) is the most common cause of acute myocardial injury and its most clinically significant form. The most effective treatment for AMI is to restore an adequate coronary blood flow to the ischemic myocardium as quickly as possible. However, reperfusion [...] Read more.
Acute myocardial infarction (AMI) is the most common cause of acute myocardial injury and its most clinically significant form. The most effective treatment for AMI is to restore an adequate coronary blood flow to the ischemic myocardium as quickly as possible. However, reperfusion of an ischemic region can induce cardiomyocyte death, a phenomenon termed “myocardial ischemia/reperfusion (I/R) injury”. Disruption of cardiac parasympathetic (vagal) activity is a common hallmark of a variety of cardiovascular diseases including AMI. Experimental studies have shown that increased vagal activity exerts cardioprotective effects against myocardial I/R injury. In addition, acetylcholine (ACh), the principle cardiac vagal neurotransmitter, has been shown to replicate the cardioprotective effects of cardiac ischemic conditioning. Moreover, studies have shown that cardiomyocytes can synthesize and secrete ACh, which gives further evidence concerning the importance of the non-neuronal cholinergic signaling cascades. This suggests that the activation of ACh receptors is involved in cardioprotection against myocardial I/R injury. There are two types of ACh receptors (AChRs), namely muscarinic and nicotinic receptors (mAChRs and nAChRs, respectively). However, the effects of AChRs activation in cardioprotection during myocardial I/R are still not fully understood. In this review, we summarize the evidence suggesting the association between AChRs activation with both electrical and pharmacological interventions and the cardioprotection during myocardial I/R, as well as outline potential mechanisms underlying these cardioprotective effects. Full article
(This article belongs to the Special Issue GPCR Structure and Function in Disease)
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