Compartmentalization of GPCR signalling controls unique cellular responses

2016 ◽  
Vol 44 (2) ◽  
pp. 562-567 ◽  
Author(s):  
Andrew M. Ellisdon ◽  
Michelle L. Halls
Keyword(s):  
Drug Discovery ◽  
Drug Targets ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Attrition Rates ◽  
Physiological Processes ◽  
Simple Chain ◽  
G Protein Coupled ◽  
Major Drug ◽  
Very High

With >800 members, G protein-coupled receptors (GPCRs) are the largest class of cell-surface signalling proteins, and their activation mediates diverse physiological processes. GPCRs are ubiquitously distributed across all cell types, involved in many diseases and are major drug targets. However, GPCR drug discovery is still characterized by very high attrition rates. New avenues for GPCR drug discovery may be provided by a recent shift away from the traditional view of signal transduction as a simple chain of events initiated from the plasma membrane. It is now apparent that GPCR signalling is restricted to highly organized compartments within the cell, and that GPCRs activate distinct signalling pathways once internalized. A high-resolution understanding of how compartmentalized signalling is controlled will probably provide unique opportunities to selectively and therapeutically target GPCRs.

G-Protein-Coupled Receptors in Drug Discovery: Nanosizing Using Cell-Free Technologies and Molecular Biology Approaches

2005 ◽  
Vol 10 (8) ◽  
pp. 765-779 ◽  
Author(s):  
Wayne R. Leifert ◽  
Amanda L. Aloia ◽  
Olgatina Bucco ◽  
Richard V. Glatz ◽  
Edward J. McMurchie
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Molecular Switching ◽  
Physiological Processes ◽  
Current Cell ◽  
G Protein Coupled ◽  
Signaling Components

Signal transduction by G-protein-coupled receptors (GPCRs) underpins a multitude of physiological processes. Ligand recognition by the receptor leads to activation of a genericmolecular switch involving heterotrimeric G-proteins and guanine nucleotides. Signal transduction has been studied extensively with both cell-based systems and assays comprising isolated signaling components. Interest and commercial investment in GPCRs in areas such as drug targets, orphan receptors, highthroughput screening, biosensors, and so on will focus greater attention on assay development to allow for miniaturization, ultra-high throughput and, eventually, microarray/biochip assay formats. Although cell-based assays are adequate for many GPCRs, it is likely that these formatswill limit the development of higher density GPCRassay platforms mandatory for other applications. Stable, robust, cell-free signaling assemblies comprising receptor and appropriate molecular switching components will form the basis of future GPCR assay platforms adaptable for such applications as microarrays. The authors review current cell-free GPCR assay technologies and molecular biological approaches for construction of novel, functional GPCR assays.

scholarly journals Advances in the molecular understanding of G protein-coupled receptors and their future therapeutic opportunities

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Daniel N. Obot ◽  
Godswill J. Udom ◽  
Anwanabasi E. Udoh ◽  
Nkechi J. Onyeukwu ◽  
Ayobami J. Olusola ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Drug Targets ◽  
Inflammatory Diseases ◽  
G Protein Coupled Receptors ◽  
Main Body ◽  
Target Class ◽  
Proper Diagnosis ◽  
Approved Drugs ◽  
G Protein Coupled

Abstract Background Understanding the mechanisms, activated and inhibited pathways as well as other molecular targets involved in existing and emerging disease conditions provides useful insights into their proper diagnosis and treatment and aids drug discovery, development and production. G protein-coupled receptors (GPCRs) are one of the most important classes of targets for small-molecule drug discovery. Of all drug targets, GPCRs are the most studied, undoubtedly because of their pharmacological tractability and role in the pathophysiology as well as the pathogenesis of human diseases. Main body of the abstract GPCRs are regarded as the largest target class of the “druggable genome” representing approximately 19% of the currently available drug targets. They have long played a prominent role in drug discovery, such that as of this writing, 481 drugs (about 34% of all FDA-approved drugs) act on GPCRs. More than 320 therapeutic agents are currently under clinical trials, of which a significant percentage targets novel GPCRs. GPCRs are implicated in a wide variety of diseases including CNS disorders, inflammatory diseases such as rheumatoid arthritis and Crohn’s disease, as well as metabolic disease and cancer. The non-olfactory human GPCRs yet to be clinically explored or tried are endowed with perhaps a huge untapped potential drug discovery especially in the field of immunology and genetics. Short conclusion This review discusses the recent advances in the molecular pharmacology and future opportunities for targeting GPCRs with a view to drug development.

scholarly journals Proton-sensing G protein-coupled receptors: detectors of tumor acidosis and candidate drug targets

2020 ◽  
Vol 12 (6) ◽  
pp. 523-532 ◽  
Author(s):  
Paul A Insel ◽  
Krishna Sriram ◽  
Cristina Salmerón ◽  
Shu Z Wiley
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Tumor Biology ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Specific Cell ◽  
Tumor Microenvironments ◽  
Candidate Drug ◽  
Survival And Growth ◽  
G Protein Coupled

Cells in tumor microenvironments (TMEs) use several mechanisms to sense their low pH (<7.0), including via proton-sensing G protein-coupled receptors (psGPCRs): GPR4, GPR65/TDAG8, GPR68/OGR1 and GPR132/G2A. Numerous cancers have increased expression of psGPCRs. The psGPCRs may contribute to features of the malignant phenotype via actions on specific cell-types in the TME and thereby promote tumor survival and growth. Here, we review data regarding psGPCR expression in tumors and cancer cells, impact of psGPCRs on survival in solid tumors and a bioinformatics approach to infer psGPCR expression in cell types in the TME. New tools are needed to help define contributions of psGPCRs in tumor biology and to identify potentially novel therapeutic agents for a variety of cancers.

scholarly journals GRK2/3/5/6 knockout: The impact of individual GRKs on arrestin-binding and GPCR regulation

2021 ◽  
Author(s):  
J. Drube ◽  
R.S. Haider ◽  
E.S.F. Matthees ◽  
M. Reichel ◽  
J. Zeiner ◽  
...  
Keyword(s):  
Drug Targets ◽  
Statistical Evaluation ◽  
G Protein Coupled Receptors ◽  
Transmembrane Receptors ◽  
Cell Clones ◽  
Ligand Stimulation ◽  
Complex Regulation ◽  
The Impact ◽  
G Protein Coupled ◽  
Major Drug

AbstractG protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors and represent major drug targets. Upon ligand stimulation, GPCRs activate G proteins and undergo a complex regulation by interaction with GPCR kinases (GRKs) and formation of receptor–arrestin complexes. For many GPCRs, this mechanism triggers receptor desensitisation, internalisation, and possibly a second intracellular signalling wave. Here we created eleven different HEK293 knockout cell clones for GRK2, 3, 5, and 6 individually and in combination. These include four single, two double, four triple, and the quadruple GRK knockout. The statistical evaluation of β-arrestin1/2 interactions for twelve different receptors grouped the tested GPCRs into two main subsets: those for which β-arrestin interaction was mediated by either GRK2, 3, 5, or 6 and those that are mediated by GRK2 or 3 only. Interestingly, the overexpression of specific GRKs was found to induce a robust, ligand-independent β-arrestin interaction with the V2R and AT1R. Finally, using GRK knockout cells, PKC inhibitors, and β-arrestin mutants, we present evidence for differential AT1R–β-arrestin2 complex configurations mediated by selective engagement of PKC, GRK2, or GRK6. We anticipate our novel GRK-knockout platform to facilitate the elucidation of previously unappreciated details of GRK-specific GPCR regulation and β-arrestin complex formation.

scholarly journals Bovine Serum Albumin-Estrogen Compounds Differentially Alter Gonadotropin-Releasing Hormone-1 Neuronal Activity

Endocrinology ◽  
2005 ◽  
Vol 146 (2) ◽  
pp. 558-563 ◽  
Author(s):  
Jennifer L. Temple ◽  
Susan Wray
Keyword(s):  
Steroid Hormones ◽  
Gene Transcription ◽  
Neuronal Activity ◽  
Calcium Imaging ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Binding Properties ◽  
Physiological Processes ◽  
17Β Estradiol ◽  
G Protein Coupled

Abstract Steroid hormones regulate a host of physiological processes and behaviors. These actions can occur by genomic mechanisms involving gene transcription or by nongenomic mechanisms proposed to involve receptors associated with the plasma membrane. BSA-conjugated steroid hormones have been extensively used to elucidate signal transduction pathways for these hormones. We have previously shown, using calcium imaging, that 17β-estradiol (E2) significantly increases GnRH-1 neuronal activity. During the course of these experiments, it became apparent that three different BSA-estrogen compounds have been used in a variety of cell types: 17β-estradiol 6-O-carboxymethyloxime-BSA (E2-6-BSA); 1,3,5(10)-estratrien-3,16α,17β-triol-6-one 6-O-carboxymethyloxime-BSA (E-6-BSA); and 1,3,5(10)-estratrien-3,17β-diol 17-hemisuccinate-BSA (E2-17-BSA). The effects of these compounds on GnRH-1 neuronal activity were compared using calcium imaging. E-6-BSA and E2-17-BSA, but not E2-6-BSA, significantly increased all parameters of GnRH-1 neuronal activity. In addition, the effects of these two BSA compounds were reversed by the estrogen receptor antagonist ICI 182,780 but not by inhibition of gene transcription. The effects of E2-17-BSA, but not E-6-BSA were reversed by treatment with pertussis toxin, which blocks G protein-coupled receptors. These data indicate that these compounds cannot be used interchangeably and clearly have different binding properties and/or different effects on target tissues.

Carbazole Derivatives as Kinase-Targeting Inhibitors for Cancer Treatment

2020 ◽  
Vol 20 (6) ◽  
pp. 444-465 ◽  
Author(s):  
Jessica Ceramella ◽  
Domenico Iacopetta ◽  
Alexia Barbarossa ◽  
Anna Caruso ◽  
Fedora Grande ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Drug Targets ◽  
Mechanisms Of Action ◽  
Biological Pathways ◽  
G Protein Coupled Receptors ◽  
Ability To Act ◽  
Different Types ◽  
Activity Of Enzymes ◽  
Intercalating Agents ◽  
G Protein Coupled

Protein Kinases (PKs) are a heterogeneous family of enzymes that modulate several biological pathways, including cell division, cytoskeletal rearrangement, differentiation and apoptosis. In particular, due to their crucial role during human tumorigenesis and cancer progression, PKs are ideal targets for the design and development of effective and low toxic chemotherapeutics and represent the second group of drug targets after G-protein-coupled receptors. Nowadays, several compounds have been claimed to be PKs inhibitors, and some of them, such as imatinib, erlotinib and gefitinib, have already been approved for clinical use, whereas more than 30 others are in various phases of clinical trials. Among them, some natural or synthetic carbazole-based molecules represent promising PKs inhibitors due to their capability to interfere with PK activity by different mechanisms of action including the ability to act as DNA intercalating agents, interfere with the activity of enzymes involved in DNA duplication, such as topoisomerases and telomerases, and inhibit other proteins such as cyclindependent kinases or antagonize estrogen receptors. Thus, carbazoles can be considered a promising this class of compounds to be adopted in targeted therapy of different types of cancer.

scholarly journals The relevance of adhesion G protein-coupled receptors in metabolic functions

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Isabell Kaczmarek ◽  
Tomáš Suchý ◽  
Simone Prömel ◽  
Torsten Schöneberg ◽  
Ines Liebscher ◽  
...  
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Specific Expression ◽  
Physiological Functions ◽  
Metabolic Functions ◽  
Central Nervous Systems ◽  
G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

scholarly journals The Biology of Vasopressin

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 89
Author(s):  
Samantha Sparapani ◽  
Cassandra Millet-Boureima ◽  
Joshua Oliver ◽  
Kathy Mu ◽  
Pegah Hadavi ◽  
...  
Keyword(s):  
Parental Behavior ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Receptor Expression ◽  
Evolutionarily Conserved ◽  
Terrestrial Environments ◽  
Intracellular Vesicles ◽  
G Protein Coupled ◽  
Neuropsychiatric Conditions ◽  
Vasopressin Synthesis

Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists.

scholarly journals Integrating High-Content Analysis into a Multiplexed Screening Approach to Identify and Characterize GPCR Agonists

2014 ◽  
Vol 19 (7) ◽  
pp. 1079-1089 ◽  
Author(s):  
Yingjie Zhu ◽  
John Watson ◽  
Mengjie Chen ◽  
Ding Ren Shen ◽  
Melissa Yarde ◽  
...  
Keyword(s):  
Drug Discovery ◽  
G Protein Coupled Receptors ◽  
High Content Imaging ◽  
Biased Agonism ◽  
Receptor Oligomerization ◽  
Sphingosine 1 Phosphate ◽  
High Content Analysis ◽  
Screening Assays ◽  
Hit Identification ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) are one of the most popular and proven target classes for therapeutic intervention. The increased appreciation for allosteric modulation, receptor oligomerization, and biased agonism has led to the development of new assay platforms that seek to capitalize on these aspects of GPCR biology. High-content screening is particularly well suited for GPCR drug discovery given the ability to image and quantify changes in multiple cellular parameters, to resolve subcellular structures, and to monitor events within a physiologically relevant environment. Focusing on the sphingosine-1-phosphate (S1P1) receptor, we evaluated the utility of high-content approaches in hit identification efforts by developing and applying assays to monitor β-arrestin translocation, GPCR internalization, and GPCR recycling kinetics. Using these approaches in combination with more traditional GPCR screening assays, we identified compounds whose unique pharmacological profiles would have gone unnoticed if using a single platform. In addition, we identified a compound that induces an atypical pattern of β-arrestin translocation and GPCR recycling kinetics. Our results highlight the value of high-content imaging in GPCR drug discovery efforts and emphasize the value of a multiassay approach to study pharmacological properties of compounds of interest.

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