NPY, ET-1, and Ang II nuclear receptors in human endocardial endothelial cellsThis 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. 299-307 ◽  
Author(s):  
Danielle Jacques ◽  
Sawsan Sader ◽  
Claudine Perreault ◽  
Dima Abdel-Samad ◽  
Farah Jules ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Ang Ii ◽  
Special Issue ◽  
A Cell ◽  
Endocardial Endothelial Cells ◽  
Plasma Membrane Receptors ◽  
G Protein Coupled ◽  
Selection Of

Neuropeptide Y (NPY), endothelin-1 (ET-1), and angiotensin II (Ang II) are peptides that are known to play many important roles in cardiovascular homeostasis. The physiological actions of these peptides are thought to be primarily mediated by plasma membrane receptors that belong to the G-protein-coupled receptor superfamily. However, there is increasing evidence that suggests the existence of functional G-protein-coupled receptors at the level of the nucleus and that the nucleus could be a cell within a cell. Here, we review our work showing the presence in the nucleus of the NPY Y1 receptor, the ETA and ETB receptors, as well as the AT1 and AT2 receptors and their respective ligands. This work was carried out in 20-week-old fetal human endocardial endothelial cells. Our results demonstrate that nuclear Y1, AT1, and ETA receptors modulate nuclear calcium in these cells.

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 signalling at the cell nucleus: an emerging paradigmThis 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. 287-297 ◽  
Author(s):  
Fernand Gobeil ◽  
Audrey Fortier ◽  
Tang Zhu ◽  
Michela Bossolasco ◽  
Martin Leduc ◽  
...  
Keyword(s):  
G Protein ◽  
Cell Nucleus ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Cell Metabolism ◽  
Hormone Secretion ◽  
G Protein Coupled Receptors ◽  
A Cell ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

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.

Selective recruitment of arrestin-3 to clathrin coated pits upon stimulation of G protein-coupled receptors

2000 ◽  
Vol 113 (13) ◽  
pp. 2463-2470 ◽  
Author(s):  
F. Santini ◽  
R.B. Penn ◽  
A.W. Gagnon ◽  
J.L. Benovic ◽  
J.H. Keen
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Coated Pits ◽  
Over Expression ◽  
Physiological Conditions ◽  
A Cell ◽  
G Protein Coupled ◽  
Comparable Magnitude

Non-visual arrestins (arrestin-2 and arrestin-3) play critical roles in the desensitization and internalization of many G protein-coupled receptors. In vitro experiments have shown that both non-visual arrestins bind with high and approximately comparable affinities to activated, phosphorylated forms of receptors. They also exhibit high affinity binding, again of comparable magnitude, to clathrin. Further, agonist-promoted internalization of many receptors has been found to be stimulated by exogenous over-expression of either arrestin2 or arrestin3. The existence of multiple arrestins raises the question whether stimulated receptors are selective for a specific endogenous arrestin under more physiological conditions. Here we address this question in RBL-2H3 cells, a cell line that expresses comparable levels of endogenous arrestin-2 and arrestin-3. When (beta)(2)-adrenergic receptors are stably expressed in these cells the receptors internalize efficiently following agonist stimulation. However, by immunofluorescence microscopy we determine that only arrestin-3, but not arrestin-2, is rapidly recruited to clathrin coated pits upon receptor stimulation. Similarly, in RBL-2H3 cells that stably express physiological levels of m1AChR, the addition of carbachol selectively induces the localization of arrestin-3, but not arrestin-2, to coated pits. Thus, this work demonstrates coupling of G protein-coupled receptors to a specific non-visual arrestin in an in vivo setting.

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.

Expression of G protein coupled receptors in a cell-free translational system using detergents and thioredoxin-fusion vectors

2005 ◽  
Vol 41 (1) ◽  
pp. 27-37 ◽  
Author(s):  
Goshi Ishihara ◽  
Mie Goto ◽  
Mihoro Saeki ◽  
Kaori Ito ◽  
Tetsuya Hori ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
A Cell ◽  
G Protein Coupled

scholarly journals Identification and Functional Analysis of G Protein-Coupled Receptors in 20-Hydroxyecdysone Signaling From the Helicoverpa armigera Genome

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan-Li Li ◽  
Yan-Xue Li ◽  
Xiao-Pei Wang ◽  
Xin-Le Kang ◽  
Ke-Qin Guo ◽  
...  
Keyword(s):  
G Protein ◽  
Helicoverpa Armigera ◽  
Hormone Receptor ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Pest Species ◽  
Metamorphic Stage ◽  
Adipokinetic Hormone ◽  
Helicoverpa Armígera ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors in animals and humans, which transmit various signals from the extracellular environment into cells. Studies have reported that several GPCRs transmit the same signal; however, the mechanism is unclear. In the present study, we identified all 122 classical GPCRs from the genome of Helicoverpa armigera, a lepidopteran pest species. Twenty-four GPCRs were identified as upregulated at the metamorphic stage by comparing the transcriptomes of the midgut at the metamorphic and feeding stages. Nine of them were confirmed to be upregulated at the metamorphic stage. RNA interference in larvae revealed the prolactin-releasing peptide receptor (PRRPR), smoothened (SMO), adipokinetic hormone receptor (AKHR), and 5-hydroxytryptamine receptor (HTR) are involved in steroid hormone 20-hydroxyecdysone (20E)-promoted pupation. Frizzled 7 (FZD7) is involved in growth, while tachykinin-like peptides receptor 86C (TKR86C) had no effect on growth and pupation. Via these GPCRs, 20E regulated the expression of different genes, respectively, including Pten (encoding phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase), FoxO (encoding forkhead box O), BrZ7 (encoding broad isoform Z7), Kr-h1 (encoding Krüppel homolog 1), Wnt (encoding Wingless/Integrated) and cMyc, with hormone receptor 3 (HHR3) as their common regulating target. PRRPR was identified as a new 20E cell membrane receptor using a binding assay. These data suggested that 20E, via different GPCRs, regulates different gene expression to integrate growth and development.

scholarly journals Candesartan abrogates G protein-coupled receptors agonist-induced MAPK activation and cardiac myocyte hypertrophy

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S154-S161 ◽  
Author(s):  
Djamel Lebeche ◽  
Zhao Bin Kang ◽  
Roger Hajjar
Keyword(s):  
Cardiac Hypertrophy ◽  
G Protein ◽  
Map Kinases ◽  
At1 Receptor ◽  
G Protein Coupled Receptors ◽  
Neonatal Rat ◽  
Leucine Incorporation ◽  
Dependent Manner ◽  
Ang Ii ◽  
G Protein Coupled

The renin-angiotensin-aldosterone system (RAAS) has been identified as a major contributor to the development of cardiac hypertrophy and the subsequent transition to heart failure. G protein-coupled receptors agonists such as angiotensin II (Ang II), endothelin-1 (ET-1) and phenylephrine (PE) have been implicated in hypertrophic responses in ventricular myocytes through the activation of several families of MAP kinases. In this study we examined the effect of candesartan, an Ang II type 1-(AT1)-receptor antagonist, on cardiac hypertrophy by using cultured neonatal rat cardiomyocytes. Stimulation with Ang II (100 nM), ET-1 (100 nM) or PE (1 µM) induced marked increases in [3H]Leucine incorporation (≥ 50%), compatible with enhanced protein synthesis. The addition of candesartan abrogated the increase in [3H]Leucine incorporation in response not only to Ang II but also to ET-1 and PE. To elucidate the mechanisms involved in this antihypertrophic effect of candesartan, we studied the activation of p38-MAPK, extracellular signal-regulated kinases (ERK1/2) and stress-activated protein kinases (SAPKs). Ang II, ET-1 and PE increased the phosphorylation levels of ERK1/2, p54 SAPK and p46SAPK and p38 in a time-dependent manner. This activation was completely blocked in the case of Ang II by pretreatment with candesartan. ET-1-induced activation of ERKs, SAPKs and p38 was also partially, but significantly, reduced by candesartan. PE-induced activation of SAPKs, but not ERKs and p38, was also reduced by candesartan. These results suggest that the hypertrophic response to ET-1 and PE, along with Ang II, is dependent upon a functioning AT1-receptor and may be mediated by AT 1 activation of the MAP kinases.

scholarly journals G protein-coupled receptors function as cell membrane receptors for the steroid hormone 20-hydroxyecdysone

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiao-Fan Zhao
Keyword(s):  
Cell Membrane ◽  
Steroid Hormones ◽  
G Protein ◽  
Steroid Hormone ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Research Progress ◽  
Nongenomic Action ◽  
Signaling Axis ◽  
G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) are cell membrane receptors for various ligands. Recent studies have suggested that GPCRs transmit animal steroid hormone signals. Certain GPCRs have been shown to bind steroid hormones, for example, G protein-coupled estrogen receptor 1 (GPER1) binds estrogen in humans, and Drosophila dopamine/ecdysteroid receptor (DopEcR) binds the molting hormone 20-hydroxyecdysone (20E) in insects. This review summarizes the research progress on GPCRs as animal steroid hormone cell membrane receptors, including the nuclear and cell membrane receptors of steroid hormones in mammals and insects, the 20E signaling cascade via GPCRs, termination of 20E signaling, and the relationship between genomic action and the nongenomic action of 20E. Studies indicate that 20E induces a signal via GPCRs to regulate rapid cellular responses, including rapid Ca2+ release from the endoplasmic reticulum and influx from the extracellular medium, as well as rapid protein phosphorylation and subcellular translocation. 20E via the GPCR/Ca2+/PKC/signaling axis and the GPCR/cAMP/PKA-signaling axis regulates gene transcription by adjusting transcription complex formation and DNA binding activity. GPCRs can bind 20E in the cell membrane and after being isolated, suggesting GPCRs as cell membrane receptors of 20E. This review deepens our understanding of GPCRs as steroid hormone cell membrane receptors and the GPCR-mediated signaling pathway of 20E (20E-GPCR pathway), which will promote further study of steroid hormone signaling via GPCRs, and presents GPCRs as targets to explore new pharmaceutical materials to treat steroid hormone-related diseases or control pest insects. Graphical abstract

G protein-coupled receptors serve as mechanosensors for fluid shear stress in neutrophils

2006 ◽  
Vol 290 (6) ◽  
pp. C1633-C1639 ◽  
Author(s):  
Ayako Makino ◽  
Eric R. Prossnitz ◽  
Moritz Bünemann ◽  
Ji Ming Wang ◽  
Weijuan Yao ◽  
...  
Keyword(s):  
Shear Stress ◽  
G Protein ◽  
Fluid Shear Stress ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Specific Response ◽  
Constitutive Activity ◽  
Fluid Shear ◽  
Hl60 Cells ◽  
G Protein Coupled

Many cells respond to fluid shear stress but in a cell type-specific fashion. Fluid shear stress applied to leukocytes serves to control pseudopod formation, migration, and other functions. Specifically, fresh neutrophils or neutrophilic leukocytes derived from differentiated HL60 cells respond to fluid shear stress by cytoplasmic pseudopod retraction. The membrane elements that sense fluid shear and induce such a specific response are still unknown, however. We hypothesized that membrane receptors may serve as fluid shear sensors. We found that fluid shear decreased the constitutive activity of G protein-coupled receptors (GPCRs). Inhibition of GPCR constitutive activity by inverse agonists abolished fluid shear stress-induced cell area reduction. Among the GPCRs in neutrophils, the formyl peptide receptor (FPR) exhibits relatively high constitutive activity. Undifferentiated HL60 cells that lacked FPR formed few pseudopods and showed no detectable response to fluid shear stress, whereas expression of FPR in undifferentiated HL60 cells caused pseudopod projection and robust pseudopod retraction during fluid shear. FPR small interfering RNA-transfected differentiated HL60 cells exhibited no response to fluid shear stress. These results suggest that GPCRs serve as mechanosensors for fluid shear stress in neutrophils by decreasing its constitutive activity and reducing pseudopod projection.

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