scholarly journals EJE AWARD 2020: Signalling by G protein-coupled receptors: why space and time matter

2021 ◽  
Vol 184 (2) ◽  
pp. R41-R49
Author(s):  
Davide Calebiro
Keyword(s):  
G Protein ◽  
Single Molecule ◽  
Drug Targets ◽  
Endocrine System ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Optical Methods ◽  
Endocrine Disorders ◽  
Spatiotemporal Resolution ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and major drug targets. They play a fundamental role in the endocrine system, where they mediate the effects of several hormones and neurotransmitters. As a result, alterations of GPCR signalling are a major cause of endocrine disorders such as congenital hypothyroidism or Cushing’s syndrome. My group develops innovative optical methods such as fluorescence resonance energy transfer (FRET) and single-molecule microscopy, which allow us to investigate GPCR signalling in living cells with unprecedented spatiotemporal resolution. Using this innovative approach, we have contributed to elucidate some long-debated questions about the mechanisms of GPCR signalling and their involvement in human disease. Among other findings, these studies have led to the unexpected discovery that GPCRs are not only signalling at the cell surface, as previously assumed, but also at various intracellular sites. This has important implications to understand how hormones and neurotransmitters produce specific responses in our cells and might pave the way to innovative treatments for common diseases like diabetes or heart failure.

scholarly journals Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

2010 ◽  
Vol 45 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Davide Calebiro ◽  
Viacheslav O Nikolaev ◽  
Martin J Lohse
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
Current Model ◽  
Living Cells ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Optical Methods ◽  
Camp Signaling ◽  
Gpcr Signaling ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

scholarly journals Regulation of G Protein-Coupled Receptors by Ubiquitination

2017 ◽  
Author(s):  
Kamila Skieterska ◽  
Pieter Rondou ◽  
Kathleen Van Craenenbroeck
Keyword(s):  
G Protein ◽  
Posttranslational Modifications ◽  
Drug Targets ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Deubiquitinating Enzymes ◽  
Range Of Functions ◽  
Beta Arrestins ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors that control many cellular processes and consequently often serve as drug targets. These receptors undergo a strict regulation by mechanisms such as internalization and desensitization, which are strongly influenced by posttranslational modifications. Ubiquitination is a posttranslational modification with a broad range of functions that is currently gaining increased appreciation as a regulator of GPCR activity. The role of ubiquitination in directing GPCRs for lysosomal degradation has already been well-established. Furthermore, this modification can also play a role in targeting membrane and endoplasmic reticulum-associated receptors to the proteasome. Most recently, ubiquitination was also shown to be involved in GPCR signaling. In this review, we present current knowledge on the molecular basis of GPCR regulation by ubiquitination, and highlight the importance of E3 ubiquitin ligases, deubiquitinating enzymes and β-arrestins. Finally, we discuss classical and newly-discovered functions of ubiquitination in controlling GPCR activity.

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 Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

2021 ◽  
Vol 22 (22) ◽  
pp. 12329
Author(s):  
Alfredo Ulloa-Aguirre ◽  
Teresa Zariñán ◽  
Eduardo Jardón-Valadez
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Therapeutic Interventions ◽  
Endocrine Function ◽  
Receptor Protein ◽  
G Protein Coupled

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

scholarly journals Actin filaments partition primary cilia membranes into distinct fluid corrals

2018 ◽  
Vol 217 (8) ◽  
pp. 2831-2849 ◽  
Author(s):  
Sungsu Lee ◽  
Han Yen Tan ◽  
Ivayla I. Geneva ◽  
Aleksandr Kruglov ◽  
Peter D. Calvert
Keyword(s):  
Diffusion Coefficient ◽  
G Protein ◽  
Primary Cilia ◽  
Super Resolution ◽  
G Protein Coupled Receptors ◽  
Membrane Diffusion ◽  
Filamentous Actin ◽  
Spatiotemporal Resolution ◽  
Fast Tracking ◽  
G Protein Coupled

Physical properties of primary cilia membranes in living cells were examined using two independent, high-spatiotemporal-resolution approaches: fast tracking of single quantum dot–labeled G protein–coupled receptors and a novel two-photon super-resolution fluorescence recovery after photobleaching of protein ensemble. Both approaches demonstrated the cilium membrane to be partitioned into corralled domains spanning 274 ± 20 nm, within which the receptors are transiently confined for 0.71 ± 0.09 s. The mean membrane diffusion coefficient within the corrals, Dm1 = 2.9 ± 0.41 µm2/s, showed that the ciliary membranes were among the most fluid encountered. At longer times, the apparent membrane diffusion coefficient, Dm2 = 0.23 ± 0.05 µm2/s, showed that corral boundaries impeded receptor diffusion 13-fold. Mathematical simulations predict the probability of G protein–coupled receptors crossing corral boundaries to be 1 in 472. Remarkably, latrunculin A, cytochalasin D, and jasplakinolide treatments altered the corral permeability. Ciliary membranes are thus partitioned into highly fluid membrane nanodomains that are delimited by filamentous actin.

scholarly journals Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

2019 ◽  
Vol 20 (6) ◽  
pp. 1402 ◽  
Author(s):  
Antonella Di Pizio ◽  
Maik Behrens ◽  
Dietmar Krautwurst
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Current Knowledge ◽  
Chemical Space ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Odorant Receptors ◽  
Taste Receptors ◽  
Umami Taste ◽  
G Protein Coupled

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.

Intracrine signaling through lipid mediators and their cognate nuclear G-protein-coupled receptors: a paradigm based on PGE2, PAF, and LPA1 receptorsThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

2006 ◽  
Vol 84 (3-4) ◽  
pp. 377-391 ◽  
Author(s):  
Tang Zhu ◽  
Fernand Gobeil ◽  
Alejandro Vazquez-Tello ◽  
Martin Leduc ◽  
Lenka Rihakova ◽  
...  
Keyword(s):  
G Protein ◽  
Nuclear Localization ◽  
Platelet Activating Factor ◽  
Rat Hepatocytes ◽  
Lipid Mediators ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Surface Receptors ◽  
A Cell ◽  
G Protein Coupled

Prostaglandins (PGs), platelet-activating factor (PAF), and lysophosphatidic acid (LPA) are ubiquitous lipid mediators that play important roles in inflammation, cardiovascular homeostasis, and immunity and are also known to modulate gene expression of specific pro-inflammatory genes. The mechanism of action of these lipids is thought to be primarily dependent on their specific plasma membrane receptors belonging to the superfamily of G-protein-coupled receptors (GPCR). Increasing evidence suggests the existence of a functional intracellular GPCR population. It has been proposed that immediate effects are mediated via cell surface receptors whereas long-term responses are dependent upon intracellular receptor effects. Indeed, receptors for PAF, LPA, and PGE2 (specifically EP1, EP3, and EP4) localize at the cell nucleus of cerebral microvascular endothelial cells of newborn pigs, rat hepatocytes, and cells overexpressing each receptor. Stimulation of isolated nuclei with these lipids reveals biological functions including transcriptional regulation of major genes, namely c-fos, cylooxygenase-2, and endothelial as well as inducible nitric oxide synthase. In the present review, we shall focus on the nuclear localization and signaling of GPCRs recognizing PGE2, PAF, and LPA phospholipids as ligands. Mechanisms on how nuclear PGE2, PAF, and LPA receptors activate gene transcription and nuclear localization pathways are presented. Intracrine signaling for lipid mediators uncover novel pathways to elicit their effects; accordingly, intracellular GPCRs constitute a distinctive mode of action for gene regulation.

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.

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