Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
8.3
5.5
Journals
Biomolecules
Special Issues
Molecular Mechanisms of Compartmentalized GPCR Signaling
share announcement

Molecular Mechanisms of Compartmentalized GPCR Signaling

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 24270

Special Issue Editors

Dr. Paolo Annibale

E-Mail Website
Guest Editor
1. Max-Delbrück-Centrum für Molekulare Medizin (MDC), Robert-Rössle-Straße, 10 13125 Berlin, Germany
2. School of Physics and Astronomy, University of St Andrews, St Andrews KY16 9AJ, UK
Interests: G protein-coupled Receptors; fluorescence spectroscopy; signal compartmentalization; single cell imaging
Dr. Marco Scarselli

E-Mail Website
Co-Guest Editor
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56128 Pisa, Italy
Interests: GPCRs; neurodegenerative disorders; psychiatric disorders; antipsychotics; mood stabilizers; antidepressants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) comprise the largest family of membrane receptors and are prominent drug targets, as they mediate a significant portion of cell-to-cell signaling (Hauser et al, 2017).

While the diversity of the family reflects the abundance of signaling molecules, most GPCR-mediated signaling events result in relatively few common downstream pathways (Wacker et al, 2017; Maudsley et al, 2005).

Individual cells are remarkably capable of distinguishing and integrating signals and cues originating from distinct receptors, even if they rely on common second messengers, leading to the notion of signal compartmentalization. However, signal compartmentalization may arise at different levels, including (i) receptor spatiotemporal compartmentalization at the subcellular level; (ii) the local modulation of the interaction of the receptors with their downstream signaling partners; and (iii) the compartmentalization of the second messengers (Calebiro et al, 2019; Bers et al, 2018).

Although second messenger compartmentalization has, by far, received the most attention to date (Netwon et al, 2016), emerging evidence suggests that signal compartmentalization can occur also upstream in the signaling cascade, often modulated by the complex biophysical environment at or near the cell plasma membrane (Hilgendorf et al, 2016), or by the interactions of the receptors with themselves (Milligan 2009) and/or with accessory proteins (Hay et al, 2016).

In this issue we are particularly interested in reports and novel evidence addressing the first two points, namely the compartmentalization of receptors and their signaling partners at the plasma membrane and the local modulation of their interactions. Since most recent advances in this field have been driven by the widespread application of high spatial- and temporal-resolution optical microscopies, we will particularly welcome research reporting on novel imaging approaches, fluorescence labeling tools and technologies for addressing this question.

Dr. Paolo Annibale
Prof. Marco Scarselli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • G-protein-coupled Receptors
  • fluorescence spectroscopy
  • signal compartmentalization
  • single cell imaging

Published Papers (7 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

23 pages, 14988 KiB  
Article
Expression Mapping and Functional Analysis of Orphan G-Protein-Coupled Receptor GPR158 in the Adult Mouse Brain Using a GPR158 Transgenic Mouse
by Jinlong Chang, Ze Song, Shoupeng Wei, Yunxia Zhou, Jun Ju, Peijia Yao, Youheng Jiang, Hui Jin, Xinjin Chi and Ningning Li
Biomolecules 2023, 13(3), 479; https://doi.org/10.3390/biom13030479 - 05 Mar 2023
Cited by 4 | Viewed by 2867
Abstract
Aberrant expression of G-protein-coupled receptor 158 (GPR158) has been reported to be inextricably linked to a variety of diseases affecting the central nervous system, including Alzheimer’s disease (AD), depression, intraocular pressure, and glioma, but the underlying mechanism remains elusive due to a lack [...] Read more.
Aberrant expression of G-protein-coupled receptor 158 (GPR158) has been reported to be inextricably linked to a variety of diseases affecting the central nervous system, including Alzheimer’s disease (AD), depression, intraocular pressure, and glioma, but the underlying mechanism remains elusive due to a lack of biological and pharmacological tools to elaborate its preferential cellular distribution and molecular interaction network. To assess the cellular localization, expression, and function of GPR158, we generated an epitope-tagged GPR158 mouse model (GPR158Tag) that exhibited normal motor, cognitive, and social behavior, no deficiencies in social memory, and no anxiety-like behavior compared to C57BL/6J control mice at P60. Using immunofluorescence, we found that GPR158+ cells were distributed in several brain regions including the cerebral cortex, hippocampus, cerebellum, and caudate putamen. Next, using the cerebral cortex of the adult GPR158Tag mice as a representative region, we found that GPR158 was only expressed in neurons, and not in microglia, oligodendrocytes, or astrocytes. Remarkably, the majority of GPR158 was enriched in Camk2a+ neurons whilst limited expression was found in PV+ interneurons. Concomitant 3D co-localization analysis revealed that GPR158 was mainly distributed in the postsynaptic membrane, but with a small portion in the presynaptic membrane. Lastly, via mass spectrometry analysis, we identified proteins that may interact with GPR158, and the relevant enrichment pathways were consistent with the immunofluorescence findings. RNA-seq analysis of the cerebral cortex of the GPR158−/− mice showed that GPR158 and its putative interacting proteins are involved in the chloride channel complex and synaptic vesicle membrane composition. Using these GPR158Tag mice, we were able to accurately label GPR158 and uncover its fundamental function in synaptic vesicle function and memory. Thus, this model will be a useful tool for subsequent biological, pharmacological, and electrophysiological studies related to GPR158. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
►▼ Show Figures

Figure 1

13 pages, 2087 KiB  
Article
A Setmelanotide-like Effect at MC4R Is Achieved by MC4R Dimer Separation
by Nanina Reininghaus, Sarah Paisdzior, Friederike Höpfner, Sabine Jyrch, Cigdem Cetindag, Patrick Scheerer, Peter Kühnen and Heike Biebermann
Biomolecules 2022, 12(8), 1119; https://doi.org/10.3390/biom12081119 - 15 Aug 2022
Cited by 4 | Viewed by 2547
Abstract
Melanocortin 4 receptor (MC4R) is part of the leptin-melanocortin pathway and plays an essential role in mediating energy homeostasis. Mutations in the MC4R are the most frequent monogenic cause for obesity. Due to increasing numbers of people with excess body weight, the MC4R [...] Read more.
Melanocortin 4 receptor (MC4R) is part of the leptin-melanocortin pathway and plays an essential role in mediating energy homeostasis. Mutations in the MC4R are the most frequent monogenic cause for obesity. Due to increasing numbers of people with excess body weight, the MC4R has become a target of interest in the search of treatment options. We have previously reported that the MC4R forms homodimers, affecting receptor Gs signaling properties. Recent studies introducing setmelanotide, a novel synthetic MC4R agonist, suggest a predominant role of the Gq/11 pathway regarding weight regulation. In this study, we analyzed effects of inhibiting homodimerization on Gq/11 signaling using previously reported MC4R/CB1R chimeras. NanoBRETTM studies to determine protein–protein interaction were conducted, confirming decreased homodimerization capacities of chimeric receptors in HEK293 cells. Gq/11 signaling of chimeric receptors was analyzed using luciferase-based reporter gene (NFAT) assays. Results demonstrate an improvement of alpha-MSH-induced NFAT signaling of chimeras, reaching the level of setmelanotide signaling at wild-type MC4R (MC4R-WT). In summary, our study shows that inhibiting homodimerization has a setmelanotide-like effect on Gq/11 signaling, with chimeric receptors presenting increased potency compared to MC4R-WT. These findings indicate the potential of inhibiting MC4R homodimerization as a therapeutic target to treat obesity. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
►▼ Show Figures

Figure 1

13 pages, 4389 KiB  
Article
Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization
by Megan D. Joseph, Elena Tomas Bort, Richard P. Grose, Peter J. McCormick and Sabrina Simoncelli
Biomolecules 2021, 11(10), 1503; https://doi.org/10.3390/biom11101503 - 12 Oct 2021
Cited by 10 | Viewed by 5022
Abstract
G-protein coupled receptors (GPCRs) are known to form homo- and hetero- oligomers which are considered critical to modulate their function. However, studying the existence and functional implication of these complexes is not straightforward as controversial results are obtained depending on the method of [...] Read more.
G-protein coupled receptors (GPCRs) are known to form homo- and hetero- oligomers which are considered critical to modulate their function. However, studying the existence and functional implication of these complexes is not straightforward as controversial results are obtained depending on the method of analysis employed. Here, we use a quantitative single molecule super-resolution imaging technique named qPAINT to quantify complex formation within an example GPCR. qPAINT, based upon DNA-PAINT, takes advantage of the binding kinetics between fluorescently labelled DNA imager strands to complementary DNA docking strands coupled to protein targeting antibodies to quantify the protein copy number in nanoscale dimensions. We demonstrate qPAINT analysis via a novel pipeline to study the oligomerization of the purinergic receptor Y2 (P2Y2), a rhodopsin-like GPCR, highly expressed in the pancreatic cancer cell line AsPC-1, under control, agonistic and antagonistic conditions. Results reveal that whilst the density of P2Y2 receptors remained unchanged, antagonistic conditions displayed reduced percentage of oligomers, and smaller numbers of receptors in complexes. Yet, the oligomeric state of the receptors was not affected by agonist treatment, in line with previous reports. Understanding P2Y2 oligomerization under agonistic and antagonistic conditions will contribute to unravelling P2Y2 mechanistic action and therapeutic targeting. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
►▼ Show Figures

Figure 1

19 pages, 958 KiB  
Article
MRAP2 Interaction with Melanocortin-4 Receptor in SnakeHead (Channa argus)
by Zheng-Yong Wen, Ting Liu, Chuan-Jie Qin, Yuan-Chao Zou, Jun Wang, Rui Li and Ya-Xiong Tao
Biomolecules 2021, 11(3), 481; https://doi.org/10.3390/biom11030481 - 23 Mar 2021
Cited by 23 | Viewed by 2792
Abstract
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure. Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of MC4R. The Northern snakehead (Channa argus) is an economically important freshwater [...] Read more.
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure. Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of MC4R. The Northern snakehead (Channa argus) is an economically important freshwater fish native to East Asia. To explore potential interaction between snakehead MC4R and MRAP2, herein we cloned snakehead mc4r and mrap2. The snakehead mc4r consisted of a 984 bp open reading frame encoding a protein of 327 amino acids, while snakehead mrap2 contained a 693 bp open reading frame encoding a protein of 230 amino acids. Synteny analysis indicated that mc4r was highly conserved with similar gene arrangement, while mrap2 contained two isoforms in teleost with different gene orders. Snakehead mc4r was primarily expressed in the brain, whereas mrap2 was expressed in the brain and intestine. Snakehead mc4r and mrap2 expression was modulated by fasting and refeeding. Further pharmacological experiments showed that the cloned snakehead MC4R was functional, capable of binding to peptide agonists and increasing intracellular cAMP production in a dose-dependent manner. Snakehead MC4R exhibited high constitutive activity. MRAP2 significantly decreased basal and agonist-stimulated cAMP signaling. These findings suggest that snakehead MC4R might be involved in energy balance regulation by interacting with MRAP2. Further studies are needed to elucidate MC4R in regulating diverse physiological processes in snakehead. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
►▼ Show Figures

Figure 1

Review

Jump to: Research

22 pages, 1872 KiB  
Review
GPCRs in Intracellular Compartments: New Targets for Drug Discovery
by Irene Fasciani, Marco Carli, Francesco Petragnano, Francesco Colaianni, Gabriella Aloisi, Roberto Maggio, Marco Scarselli and Mario Rossi
Biomolecules 2022, 12(10), 1343; https://doi.org/10.3390/biom12101343 - 22 Sep 2022
Cited by 14 | Viewed by 3508
Abstract
The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their [...] Read more.
The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their signal transduction is traditionally viewed as a chain of events initiated from the plasma membrane. Furthermore, their intracellular trafficking, internalization, and recycling were considered only to regulate receptor desensitization and cell surface expression. On the contrary, accumulating data strongly suggest that GPCRs also signal from intracellular compartments. GPCRs localize in the membranes of endosomes, nucleus, Golgi and endoplasmic reticulum apparatuses, mitochondria, and cell division compartments. Importantly, from these sites they have shown to orchestrate multiple signals that regulate different cell pathways. In this review, we summarize the current knowledge of this fascinating phenomenon, explaining how GPCRs reach the intracellular sites, are stimulated by the endogenous ligands, and their potential physiological/pathophysiological roles. Finally, we illustrate several mechanisms involved in the modulation of the compartmentalized GPCR signaling by drugs and endogenous ligands. Understanding how GPCR signaling compartmentalization is regulated will provide a unique opportunity to develop novel pharmaceutical approaches to target GPCRs and potentially lead the way towards new therapeutic approaches. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
►▼ Show Figures

Figure 1

16 pages, 1314 KiB  
Review
Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers
by Roberto Maggio, Irene Fasciani, Marco Carli, Francesco Petragnano, Francesco Marampon, Mario Rossi and Marco Scarselli
Biomolecules 2021, 11(12), 1828; https://doi.org/10.3390/biom11121828 - 03 Dec 2021
Cited by 5 | Viewed by 2551
Abstract
Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex [...] Read more.
Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
►▼ Show Figures

Figure 1

22 pages, 8210 KiB  
Review
Nanoscale Sub-Compartmentalization of the Dendritic Spine Compartment
by Ana Sofía Vallés and Francisco J. Barrantes
Biomolecules 2021, 11(11), 1697; https://doi.org/10.3390/biom11111697 - 15 Nov 2021
Cited by 7 | Viewed by 3586
Abstract
Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined areas. These membrane lateral heterogeneities range from nanoscopic dimensions, often involving only a few molecular constituents, to micron-sized mesoscopic domains resulting from [...] Read more.
Compartmentalization of the membrane is essential for cells to perform highly specific tasks and spatially constrained biochemical functions in topographically defined areas. These membrane lateral heterogeneities range from nanoscopic dimensions, often involving only a few molecular constituents, to micron-sized mesoscopic domains resulting from the coalescence of nanodomains. Short-lived domains lasting for a few milliseconds coexist with more stable platforms lasting from minutes to days. This panoply of lateral domains subserves the great variety of demands of cell physiology, particularly high for those implicated in signaling. The dendritic spine, a subcellular structure of neurons at the receiving (postsynaptic) end of central nervous system excitatory synapses, exploits this compartmentalization principle. In its most frequent adult morphology, the mushroom-shaped spine harbors neurotransmitter receptors, enzymes, and scaffolding proteins tightly packed in a volume of a few femtoliters. In addition to constituting a mesoscopic lateral heterogeneity of the dendritic arborization, the dendritic spine postsynaptic membrane is further compartmentalized into spatially delimited nanodomains that execute separate functions in the synapse. This review discusses the functional relevance of compartmentalization and nanodomain organization in synaptic transmission and plasticity and exemplifies the importance of this parcelization in various neurotransmitter signaling systems operating at dendritic spines, using two fast ligand-gated ionotropic receptors, the nicotinic acetylcholine receptor and the glutamatergic receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic examples. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-7
Back to TopTop