Trafficking and Function of GPCRs in the Endosomal Compartment

Calebiro, Davide; Godbole, Amod; Lyga, Sandra

doi:10.1007/978-1-4939-1755-6_16

Cited by 18 publications

(28 citation statements)

References 11 publications

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“…Accordingly, it is assumed that only few ligand and receptor molecules are sufficient to mediate ligand-triggered signaling via G-proteins either at the plasma membrane or by intracellular signaling microdomains [42]. Hence, it was proposed that GPCR signaling depends on their assembly in specific subdomains of the plasma membrane, such as lipid raft-like microdomains or in cilia [43,44,45].…”

Section: Discussionmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Localization at the Apical Plasma Membrane Domain of Fisher Rat Thyroid Epithelial Cells Is Confined to Cilia

Szumska¹,

Qatato²,

Rehders³

et al. 2015

Eur Thyroid J

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Background: The trace amine-associated receptor 1 (Taar1) is one member of the Taar family of G-protein-coupled receptors (GPCR) accepting various biogenic amines as ligands. It has been proposed that Taar1 mediates rapid, membrane-initiated effects of thyronamines, the endogenous decarboxylated and deiodinated relatives of the classical thyroid hormones T₄ and T₃. Objectives: Although the physiological actions of thyronamines in general and 3-iodothyronamine (T₁AM) in particular are incompletely understood, studies published to date suggest that synthetic T₁AM-activated Taar1 signaling antagonizes thyromimetic effects exerted by T₃. However, the location of Taar1 is currently unknown. Methods: To fill this gap in our knowledge we employed immunofluorescence microscopy and a polyclonal antibody to detect Taar1 protein expression in thyroid tissue from Fisher rats, wild-type and taar1-deficient mice, and in the polarized FRT cells. Results: With this approach we found that Taar1 is expressed in the membranes of subcellular compartments of the secretory pathway and on the apical plasma membrane of FRT cells. Three-dimensional analyses further revealed Taar1 immunoreactivity in cilial extensions of postconfluent FRT cell cultures that had formed follicle-like structures. Conclusions: The results suggest Taar1 transport along the secretory pathway and its accumulation in the primary cilium of thyrocytes. These findings are of significance considering the increasing interest in the role of cilia in harboring functional GPCR. We hypothesize that thyronamines can reach and activate Taar1 in thyroid follicular epithelia by acting from within the thyroid follicle lumen, their potential site of synthesis, as part of a nonclassical mechanism of thyroid autoregulation.

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Section: Discussionmentioning

confidence: 99%

Trace Amine-Associated Receptor 1 Localization at the Apical Plasma Membrane Domain of Fisher Rat Thyroid Epithelial Cells Is Confined to Cilia

Szumska¹,

Qatato²,

Rehders³

et al. 2015

Eur Thyroid J

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“…This is followed by a b-arrestin-dependent wave initiated either at the cell surface from clathrin-coated pits and or from clathrin-coated vesicles and results in nonclassical signals such as ERK activation (Shenoy and Lefkowitz, 2011); ERK activation by GPCRs may, by the way, be achieved via multiple signaling pathways. A third wave has been described for an increasing number of GPCRs, which involves signaling at intracellular sites via G-proteins that appear to reside at these sites and results in intracellular cAMP signals, which may have specific physiologic outcomes (Calebiro et al, 2010(Calebiro et al, , 2015Vilardaga et al, 2014;Tsvetanova et al, 2015). This third wave is then terminated by dissociation of ligand and GPCRs in the vesicles, promoted by acidification of the vesicles, and ultimately the receptors either are degraded or recycle back to the cell surface (Vilardaga et al, 2014).…”

Section: Temporal Aspects-kinetics Along the Signaling Chainmentioning

confidence: 99%

“…This third wave is then terminated by dissociation of ligand and GPCRs in the vesicles, promoted by acidification of the vesicles, and ultimately the receptors either are degraded or recycle back to the cell surface (Vilardaga et al, 2014). The temporal sequence of these distinct signaling waves has been dissected mostly for simple cell lines, such as HEK cells, but also for some primary cells, notably thyroid follicles (Calebiro et al, 2015).…”

Section: Temporal Aspects-kinetics Along the Signaling Chainmentioning

confidence: 99%

“…A new aspect of subcellular signaling was identified a few years ago, when several GPCRs were shown to signal via G-proteins after their internalization, i.e., from internal sites (Calebiro et al, 2010(Calebiro et al, , 2015Vilardaga et al, 2014;Tsvetanova et al, 2015). Thus, this type of signaling is not only temporally but also spatially distinct from the two preceding waves of signaling .…”

Section: Spatial Aspects-receptor Localization and Spatial Signaling mentioning

confidence: 99%

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Spatial and Temporal Aspects of Signaling by G-Protein–Coupled Receptors

Lohse

Hofmann

2015

Mol Pharmacol

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Signaling by G-protein-coupled receptors is often considered a uniform process, whereby a homogeneously activated proportion of randomly distributed receptors are activated under equilibrium conditions and produce homogeneous, steady-state intracellular signals. While this may be the case in some biologic systems, the example of rhodopsin with its strictly local singlequantum mode of function shows that homogeneity in space and time cannot be a general property of G-protein-coupled systems. Recent work has now revealed many other systems where such simplicity does not prevail. Instead, a plethora of mechanisms allows much more complex patterns of receptor activation and signaling: different mechanisms of proteinprotein interaction; temporal changes under nonequilibrium conditions; localized receptor activation; and localized second messenger generation and degradation-all of which shape receptor-generated signals and permit the creation of multiple signal types. Here, we review the evidence for such pleiotropic receptor signaling in space and time.

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“…A mounting body of evidence indicates that many GPCRs are also localized inside the cell where they may couple to different signaling systems, display unique desensitization patterns, and/or exhibit distinct patterns of subcellular distribution (1)(2)(3)(4)(5). For example, GPCRs have been found on mitochondria (6), endoplasmic reticulum (ER) membranes (7), lysosomes (8,9), and on nuclear membranes (10 -12).…”

mentioning

confidence: 99%

Sequences within the C Terminus of the Metabotropic Glutamate Receptor 5 (mGluR5) Are Responsible for Inner Nuclear Membrane Localization

Jong¹,

Harmon

Kumar

et al. 2017

Journal of Biological Chemistry

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Edited by Roger J. ColbranTraditionally, G-protein-coupled receptors (GPCR) are thought to be located on the cell surface where they transmit extracellular signals to the cytoplasm. However, recent studies indicate that some GPCRs are also localized to various subcellular compartments such as the nucleus where they appear required for various biological functions. For example, the metabotropic glutamate receptor 5 (mGluR5) is concentrated at the inner nuclear membrane (INM) where it mediates Ca 2؉ changes in the nucleoplasm by coupling with G q/11 . Here, we identified a region within the C-terminal domain (amino acids 852-876) that is necessary and sufficient for INM localization of the receptor. Because these sequences do not correspond to known nuclear localization signal motifs, they represent a new motif for INM trafficking. mGluR5 is also trafficked to the plasma membrane where it undergoes re-cycling/degradation in a separate receptor pool, one that does not interact with the nuclear mGluR5 pool. Finally, our data suggest that once at the INM, mGluR5 is stably retained via interactions with chromatin. Thus, mGluR5 is perfectly positioned to regulate nucleoplasmic Ca 2؉ in situ.From their position on the cell surface, G-protein-coupled receptors (GPCRs) 3 can transform external stimuli into a broad range of signaling pathways within the cell. A mounting body of evidence indicates that many GPCRs are also localized inside the cell where they may couple to different signaling systems, display unique desensitization patterns, and/or exhibit distinct patterns of subcellular distribution (1-5). For example, GPCRs have been found on mitochondria (6), endoplasmic reticulum (ER) membranes (7), lysosomes (8, 9), and on nuclear membranes (10 -12). Certain GPCRs are even found within the nucleoplasm on nuclear bodies and/or nuclear invaginations (13-16). Although many intracellular GPCRs are activated at the cell surface and subsequently trafficked to their intracellular site, others can be activated at their subcellular location via so-called intracrine ligands that can enter cells via diffusion or be made in situ, endocytosed, and/or transported through channels or pores (12,17,18). Intracellular GPCRs can also function independently governing processes such as synaptic plasticity (19), myocyte contraction (15), and angiogenesis (16). Collectively, the present findings reinforce the notion that intracellular GPCRs play a dynamic role in generating and shaping intracellular signaling pathways.As many GPCRs are on or in the nucleus, the question arises as to how they get there. Various possibilities exist to transfer membrane proteins from the outer to the inner nuclear membrane (ONM and INM), including vesicle fusion, membrane rupture, and channel-mediated pathways. Most prominently, a diffusion-retention model has been proposed for many INM proteins (e.g. lamin B receptor (LBR)) (20,21). This model suggests that proteins synthesized in the ER rapidly diffuse laterally in the ONM, pass through peripheral channels ex...

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Trafficking and Function of GPCRs in the Endosomal Compartment

Cited by 18 publications

References 11 publications

Trace Amine-Associated Receptor 1 Localization at the Apical Plasma Membrane Domain of Fisher Rat Thyroid Epithelial Cells Is Confined to Cilia

Trace Amine-Associated Receptor 1 Localization at the Apical Plasma Membrane Domain of Fisher Rat Thyroid Epithelial Cells Is Confined to Cilia

Spatial and Temporal Aspects of Signaling by G-Protein–Coupled Receptors

Sequences within the C Terminus of the Metabotropic Glutamate Receptor 5 (mGluR5) Are Responsible for Inner Nuclear Membrane Localization

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