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G-protein Coupled Receptor Structure and Function

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Molecular Diversity".

Deadline for manuscript submissions: closed (31 January 2017) | Viewed by 61005

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Special Issue Editor

Prof. Dr. Yung Hou Wong

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Guest Editor

Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong
Interests: structure and function of G protein coupled receptors; G protein-mediated signal transduction; drug discovery

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) have long been known to regulate a vast array of biological functions that range from neurotransmission, metabolism, to sensory detection and immune defense. Being cell-surface proteins, GPCRs represent amenable drug targets that form much of the foundation of modern day pharmacology. Extensive studies on prototypical GPCRs such as rhodopsin and the β₂-adrenoceptor have enabled us to establish an overview of the structure and function of this superfamily of receptors. Yet, the complexity of GPCR signaling continues to unveil surprises throughout the past few decades. These include their ability to form homo- or heterodimers with altered signaling capacity, binding to a host of proteins that can modify their localization or function, as well as their association with numerous diseases. This Special Issue aims to provide the readers with a collection of articles that address recent developments in the realm of GPCRs.

Prof. Yung Hou Wong
Guest Editor

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Keywords

G proteins
GPCR
signal transduction
cross-talk
drug receptor

Published Papers (7 papers)

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Research

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1644 KiB

Open AccessArticle

c-Jun Contributes to Transcriptional Control of GNA12 Expression in Prostate Cancer Cells

by Udhaya Kumari Udayappan and Patrick J. Casey

Molecules 2017, 22(4), 612; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22040612 - 10 Apr 2017

Cited by 12 | Viewed by 5038

Abstract

Abstract: GNA12 is the α subunit of a heterotrimeric G protein that possesses oncogenic potential. Activated GNA12 also promotes prostate and breast cancer cell invasion in vitro and in vivo, and its expression is up-regulated in many tumors, particularly metastatic tissues. In this study, we explored the control of expression of GNA12 in prostate cancer cells. Initial studies on LnCAP (low metastatic potential, containing low levels of GNA12) and PC3 (high metastatic potential, containing high GNA12 levels) cells revealed that GNA12 mRNA levels correlated with protein levels, suggesting control at the transcriptional level. To identify potential factors controlling GNA12 transcription, we cloned the upstream 5′ regulatory region of the human GNA12 gene and examined its activity using reporter assays. Deletion analysis revealed the highest level of promoter activity in a 784 bp region, and subsequent in silico analysis indicated the presence of transcription factor binding sites for C/EBP (CCAAT/enhancer binding protein), CREB1 (cAMP-response-element-binding protein 1), and c-Jun in this minimal element for transcriptional control. A small interfering RNA (siRNA) knockdown approach revealed that silencing of c-Jun expression significantly reduced GNA12 5′ regulatory region reporter activity. In addition, chromatin immunoprecipitation assays confirmed that c-Jun binds to the GNA12 5′ regulatory region in PC3 cells. Silencing of c-Jun expression reduced mRNA and protein levels of GNA12, but not the closely-related GNA13, in prostate cancer cells. Understanding the mechanisms by which GNA12 expression is controlled may aid in the development of therapies that target key elements responsible for GNA12-mediated tumor progression. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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Open AccessArticle

Rate of Homologous Desensitization and Internalization of the GLP-1 Receptor

by Ghina Shaaban, Mabayoje Oriowo and Suleiman Al-Sabah

Molecules 2017, 22(1), 22; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22010022 - 26 Dec 2016

Cited by 6 | Viewed by 5881

Abstract

The glucagon-like peptide-1 receptor (GLP-1R) is an important target in the treatment of type 2 diabetes mellitus. The aim of this study was to compare the rate of agonist stimulated desensitization and internalization of GLP-1R. To this end, an N-terminally myc-tagged GLP-1R was stably expressed in HEK-293 cells. Homologous desensitization was assessed by measuring the cAMP response to agonist stimulation following pre-incubation with agonist for up to 120 min. Receptor internalization was monitored using an indirect ELISA-based method and confocal microscopy. Pre-incubation with GLP-1 resulted in a time-dependent loss of response to a second stimulation. Washing cells following pre-incubation failed to bring cAMP levels back to basal. Taking this into account, two desensitization rates were calculated: “apparent” (t_1/2 = 19.27 min) and “net” (t_1/2 = 2.99 min). Incubation of cells with GLP-1 also resulted in a time-dependent loss of receptor cell surface expression (t_1/2 = 2.05 min). Rapid agonist-stimulated internalization of GLP-1R was confirmed using confocal microscopy. Stimulation of GLP-1R with GLP-1 results in rapid desensitization and internalization of the receptor. Interestingly, the rate of “net” desensitization closely matches the rate of internalization. Our results suggest that agonist-bound GLP-1R continues to generate cAMP after it has been internalized. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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Review

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1006 KiB

Open AccessFeature PaperReview

Role of G Protein-Coupled Receptors in the Regulation of Structural Plasticity and Cognitive Function

by Crystal C. Y. Leung and Yung H. Wong

Molecules 2017, 22(7), 1239; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22071239 - 24 Jul 2017

Cited by 32 | Viewed by 14425

Abstract

Cognition and other higher brain functions are known to be intricately associated with the capacity of neural circuits to undergo structural reorganization. Structural remodelling of neural circuits, or structural plasticity, in the hippocampus plays a major role in learning and memory. Dynamic modifications of neuronal connectivity in the form of dendritic spine morphology alteration, as well as synapse formation and elimination, often result in the strengthening or weakening of specific neural circuits that determine synaptic plasticity. Changes in dendritic complexity and synapse number are mediated by cellular processes that are regulated by extracellular signals such as neurotransmitters and neurotrophic factors. As many neurotransmitters act on G protein-coupled receptors (GPCRs), it has become increasingly apparent that GPCRs can regulate structural plasticity through a myriad of G protein-dependent pathways and non-canonical signals. A thorough understanding of how GPCRs exert their regulatory influence on dendritic spine morphogenesis may provide new insights for treating cognitive impairment and decline in various age-related diseases. In this article, we review the evidence of GPCR-mediated regulation of structural plasticity, with a special emphasis on the involvement of common as well as distinct signalling pathways that are regulated by major neurotransmitters. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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Open AccessReview

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

by Damian Bartuzi, Agnieszka A. Kaczor and Dariusz Matosiuk

Molecules 2017, 22(7), 1188; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22071188 - 15 Jul 2017

Cited by 11 | Viewed by 5297

Abstract

In recent years, our understanding of function of G protein-coupled receptors (GPCRs) has changed from a picture of simple signal relays, transmitting only a particular signal to a particular G protein heterotrimer, to versatile machines, capable of various responses to different stimuli and being modulated by various factors. Some recent reports provide not only the data on ligands/modulators and resultant signals induced by them, but also deeper insights into exact pathways of signal migration and mechanisms of signal transmission through receptor structure. Combination of these computational and experimental data sheds more light on underlying mechanisms of signal transmission and signaling bias in GPCRs. In this review we focus on available clues on allosteric pathways responsible for complex signal processing within GPCRs structures, with particular emphasis on linking compatible in silico- and in vitro-derived data on the most probable allosteric connections. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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Open AccessReview

On the Emerging Role of the Taste Receptor Type 1 (T1R) Family of Nutrient-Sensors in the Musculoskeletal System

by Shoichiro Kokabu, Jonathan W. Lowery, Takashi Toyono, Tsuyoshi Sato and Tetsuya Yoda

Molecules 2017, 22(3), 469; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22030469 - 15 Mar 2017

Cited by 9 | Viewed by 6656

Abstract

The special sense of taste guides and guards food intake and is essential for body maintenance. Salty and sour tastes are sensed via ion channels or gated ion channels while G protein-coupled receptors (GPCRs) of the taste receptor type 1 (T1R) family sense sweet and umami tastes and GPCRs of the taste receptor type 2 (T2R) family sense bitter tastes. T1R and T2R receptors share similar downstream signaling pathways that result in the stimulation of phospholipase-C-β2. The T1R family includes three members that form heterodimeric complexes to recognize either amino acids or sweet molecules such as glucose. Although these functions were originally described in gustatory tissue, T1R family members are expressed in numerous non-gustatory tissues and are now viewed as nutrient sensors that play important roles in monitoring global glucose and amino acid status. Here, we highlight emerging evidence detailing the function of T1R family members in the musculoskeletal system and review these findings in the context of the musculoskeletal diseases sarcopenia and osteoporosis, which are major public health problems among the elderly that affect locomotion, activities of daily living, and quality of life. These studies raise the possibility that T1R family member function may be modulated for therapeutic benefit. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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4877 KiB

Open AccessReview

The Formyl Peptide Receptors: Diversity of Ligands and Mechanism for Recognition

by Hui-Qiong He and Richard D. Ye

Molecules 2017, 22(3), 455; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22030455 - 13 Mar 2017

Cited by 187 | Viewed by 12788

Abstract

The formyl peptide receptors (FPRs) are G protein-coupled receptors that transduce chemotactic signals in phagocytes and mediate host-defense as well as inflammatory responses including cell adhesion, directed migration, granule release and superoxide production. In recent years, the cellular distribution and biological functions of FPRs have expanded to include additional roles in homeostasis of organ functions and modulation of inflammation. In a prototype, FPRs recognize peptides containing N-formylated methionine such as those produced in bacteria and mitochondria, thereby serving as pattern recognition receptors. The repertoire of FPR ligands, however, has expanded rapidly to include not only N-formyl peptides from microbes but also non-formyl peptides of microbial and host origins, synthetic small molecules and an eicosanoid. How these chemically diverse ligands are recognized by the three human FPRs (FPR1, FPR2 and FPR3) and their murine equivalents is largely unclear. In the absence of crystal structures for the FPRs, site-directed mutagenesis, computer-aided ligand docking and structural simulation have led to the identification of amino acids within FPR1 and FPR2 that interact with several formyl peptides. This review article summarizes the progress made in the understanding of FPR ligand diversity as well as ligand recognition mechanisms used by these receptors. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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Open AccessFeature PaperReview

Sphingosine 1-Phosphate Receptor 1 Signaling in Mammalian Cells

by Nigel J. Pyne and Susan Pyne

Molecules 2017, 22(3), 344; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules22030344 - 23 Feb 2017

Cited by 58 | Viewed by 10137

Abstract

The bioactive lipid, sphingosine 1-phosphate (S1P) binds to a family of G protein-coupled receptors, termed S1P₁-S1P₅. These receptors function in, for example, the cardiovascular system to regulate vascular barrier integrity and tone, the nervous system to regulate neuronal differentiation, myelination and oligodendrocyte/glial cell survival and the immune system to regulate T- and B-cell subsets and trafficking. S1P receptors also participate in the pathophysiology of autoimmunity, inflammatory disease, cancer, neurodegeneration and others. In this review, we describe how S1P₁ can form a complex with G-protein and β-arrestin, which function together to regulate effector pathways. We also discuss the role of the S1P₁-Platelet derived growth factor receptor β functional complex (which deploys G-protein/β-arrestin and receptor tyrosine kinase signaling) in regulating cell migration. Possible mechanisms by which different S1P-chaperones, such as Apolipoprotein M-High-Density Lipoprotein induce biological programmes in cells are also described. Finally, the role of S1P₁ in health and disease and as a target for clinical intervention is appraised. Full article

(This article belongs to the Special Issue G-protein Coupled Receptor Structure and Function)

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