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Cell Compartment-Specific Signaling by G Protein-Coupled Receptors

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 11066

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Special Issue Editors

Dr. Philippe Marin

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Guest Editor

IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
Interests: serotonin; receptor; transporter; proteomics; signaling

Dr. Séverine Chaumont-Dubel

E-Mail Website1 Website2
Guest Editor

Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
Interests: 5-HT6 receptor; serotonin; constitutive activity; neurodevelopment. proteomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

G protein-coupled receptors (GPCRs) constitute the largest and most versatile family of membrane receptors (> 800 members have been identified in the human genome). They bind to a wide range of extracellular signals (photons, ions, small and large molecules), control virtually all pathophysiological processes, and represent the target of around 35% of marketed drugs. The initial view of GPCR signal transduction was that a few common signaling pathways emanating from GPCRs exclusively located at the cell surface converged to generate highly diffusible messengers (cAMP, IP₃, Ca²⁺) that freely propagated throughout the cytosol to produce a unique cellular response. This view began to change with a number of studies using advanced tools, such as cell compartment-specific FRET or nanobody-based biosensors, and fluorescent ligands, combined with cutting-edge imaging technologies, indicating that GPCRs signal in discrete subcellular domains. These include not only plasma membrane microdomains, such as lipid rafts, caveolae, and primary cilia, but also intracellular sites located in organelles, such as endosomes, the Golgi/trans-Golgi network, the nucleus, and even mitochondria. Studies have also established that GPCRs are part of signaling units comprising receptors spatially confined with enzymes producing and degrading cellular messengers and their target proteins. This ensures a highly localized signaling that underlies the large diversity and specificity of biological responses elicited by GPCRs. In this Special Issue, we invite you to review recent evidence of GPCR signaling in specific cell compartments and to highlight how it controls key physiological functions and how its deregulation contributes to diseases.

Dr. Philippe Marin
Dr. Séverine Chaumont-Dubel
Guest Editors

Manuscript Submission Information

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Published Papers (4 papers)

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Research

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15 pages, 1997 KiB

Open AccessFeature PaperArticle

Expression of Functional Cannabinoid Type-1 (CB₁) Receptor in Mitochondria of White Adipocytes

by Antonio C. Pagano Zottola, Ilenia Severi, Astrid Cannich, Philippe Ciofi, Daniela Cota, Giovanni Marsicano, Antonio Giordano and Luigi Bellocchio

Cells 2022, 11(16), 2582; https://doi.org/10.3390/cells11162582 - 19 Aug 2022

Cited by 10 | Viewed by 2083

Abstract

Via activation of the cannabinoid type-1 (CB₁) receptor, endogenous and exogenous cannabinoids modulate important biochemical and cellular processes in adipocytes. Several pieces of evidence suggest that alterations of mitochondrial physiology might be a possible mechanism underlying cannabinoids’ effects on adipocyte biology. Many reports suggest the presence of CB₁ receptor mRNA in both white and brown adipose tissue, but the detailed subcellular localization of CB₁ protein in adipose cells has so far been scarcely addressed. In this study, we show the presence of the functional CB₁ receptor at different subcellular locations of adipocytes from epididymal white adipose tissue (eWAT) depots. We observed that CB₁ is located at different subcellular levels, including the plasma membrane and in close association with mitochondria (mtCB₁). Functional analysis in tissue homogenates and isolated mitochondria allowed us to reveal that cannabinoids negatively regulate complex-I-dependent oxygen consumption in eWAT. This effect requires mtCB₁ activation and consequent regulation of the intramitochondrial cAMP-PKA pathway. Thus, CB₁ receptors are functionally present at the mitochondrial level in eWAT adipocytes, adding another possible mechanism for peripheral regulation of energy metabolism. Full article

(This article belongs to the Special Issue Cell Compartment-Specific Signaling by G Protein-Coupled Receptors)

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23 pages, 3676 KiB

Open AccessArticle

The Succinate Receptor SUCNR1 Resides at the Endoplasmic Reticulum and Relocates to the Plasma Membrane in Hypoxic Conditions

by Melanie Sanchez, David Hamel, Emmanuel Bajon, François Duhamel, Vikrant K. Bhosle, Tang Zhu, Jose Carlos Rivera, Rabah Dabouz, Mathieu Nadeau-Vallée, Nicholas Sitaras, David-Étienne Tremblay, Samy Omri, Tiffany Habelrih, Raphael Rouget, Xin Hou, Fernand Gobeil, Jean-Sébastien Joyal, Przemyslaw Sapieha, Grant Mitchell, Alfredo Ribeiro-Da-Silva, Mohammad Ali Mohammad Nezhady and Sylvain Chemtob Show full author list Hide full author list

Cells 2022, 11(14), 2185; https://doi.org/10.3390/cells11142185 - 13 Jul 2022

Cited by 3 | Viewed by 4043

Abstract

The GPCR SUCNR1/GPR91 exerts proangiogenesis upon stimulation with the Krebs cycle metabolite succinate. GPCR signaling depends on the surrounding environment and intracellular localization through location bias. Here, we show by microscopy and by cell fractionation that in neurons, SUCNR1 resides at the endoplasmic reticulum (ER), while being fully functional, as shown by calcium release and the induction of the expression of the proangiogenic gene for VEGFA. ER localization was found to depend upon N-glycosylation, particularly at position N8; the nonglycosylated mutant receptor localizes at the plasma membrane shuttled by RAB11. This SUCNR1 glycosylation is physiologically regulated, so that during hypoxic conditions, SUCNR1 is deglycosylated and relocates to the plasma membrane. Downstream signal transduction of SUCNR1 was found to activate the prostaglandin synthesis pathway through direct interaction with COX-2 at the ER; pharmacologic antagonism of the PGE₂ EP₄ receptor (localized at the nucleus) was found to prevent VEGFA expression. Concordantly, restoring the expression of SUCNR1 in the retina of SUCNR1-null mice renormalized vascularization; this effect is markedly diminished after transfection of the plasma membrane-localized SUCNR1 N8A mutant, emphasizing that ER localization of the succinate receptor is necessary for proper vascularization. These findings uncover an unprecedented physiologic process where GPCR resides at the ER for signaling function. Full article

(This article belongs to the Special Issue Cell Compartment-Specific Signaling by G Protein-Coupled Receptors)

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Review

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12 pages, 51425 KiB

Open AccessReview

Impact of 5-HT₆ Receptor Subcellular Localization on Its Signaling and Its Pathophysiological Roles

by Séverine Chaumont-Dubel, Sonya Galant, Matthieu Prieur, Tristan Bouschet, Joël Bockaert and Philippe Marin

Cells 2023, 12(3), 426; https://doi.org/10.3390/cells12030426 - 27 Jan 2023

Cited by 1 | Viewed by 1677

Abstract

The serotonin (5-HT)₆ receptor still raises particular interest given its unique spatio-temporal pattern of expression among the serotonin receptor subtypes. It is the only serotonin receptor specifically expressed in the central nervous system, where it is detected very early in embryonic life and modulates key neurodevelopmental processes, from neuronal migration to brain circuit refinement. Its predominant localization in the primary cilium of neurons and astrocytes is also unique among the serotonin receptor subtypes. Consistent with the high expression levels of the 5-HT₆ receptor in brain regions involved in the control of cognitive processes, it is now well-established that the pharmacological inhibition of the receptor induces pro-cognitive effects in several paradigms of cognitive impairment in rodents, including models of neurodevelopmental psychiatric disorders and neurodegenerative diseases. The 5-HT₆ receptor can engage several signaling pathways in addition to the canonical Gs signaling, but there is still uncertainty surrounding the signaling pathways that underly its modulation of cognition, as well as how the receptor’s coupling is dependent on its cellular compartmentation. Here, we describe recent findings showing how the proper subcellular localization of the receptor is achieved, how this peculiar localization determines signaling pathways engaged by the receptor, and their pathophysiological influence. Full article

(This article belongs to the Special Issue Cell Compartment-Specific Signaling by G Protein-Coupled Receptors)

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Other

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18 pages, 1561 KiB

Open AccessPerspective

The Impact of Membrane Protein Diffusion on GPCR Signaling

by Horst-Holger Boltz, Alexei Sirbu, Nina Stelzer, Primal de Lanerolle, Stefanie Winkelmann and Paolo Annibale

Cells 2022, 11(10), 1660; https://doi.org/10.3390/cells11101660 - 17 May 2022

Cited by 1 | Viewed by 2458

Abstract

Spatiotemporal signal shaping in G protein-coupled receptor (GPCR) signaling is now a well-established and accepted notion to explain how signaling specificity can be achieved by a superfamily sharing only a handful of downstream second messengers. Dozens of G

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-coupled GPCR signals ultimately [...] Read more.

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-coupled GPCR signals ultimately converge on the production of cAMP, a ubiquitous second messenger. This idea is almost always framed in terms of local concentrations, the differences in which are maintained by means of spatial separation. However, given the dynamic nature of the reaction-diffusion processes at hand, the dynamics, in particular the local diffusional properties of the receptors and their cognate G proteins, are also important. By combining some first principle considerations, simulated data, and experimental data of the receptors diffusing on the membranes of living cells, we offer a short perspective on the modulatory role of local membrane diffusion in regulating GPCR-mediated cell signaling. Our analysis points to a diffusion-limited regime where the effective production rate of activated G protein scales linearly with the receptor–G protein complex’s relative diffusion rate and to an interesting role played by the membrane geometry in modulating the efficiency of coupling. Full article

(This article belongs to the Special Issue Cell Compartment-Specific Signaling by G Protein-Coupled Receptors)

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