Lysophosphatidylinositol: a novel link between ABC transporters and G-protein-coupled receptors

2014 ◽  
Vol 42 (5) ◽  
pp. 1372-1377 ◽  
Author(s):  
Emily L. Ruban ◽  
Riccardo Ferro ◽  
Syamsul Ahmad Arifin ◽  
Marco Falasca
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Cancer Progression ◽  
Multidrug Resistance Protein 1 ◽  
Autocrine Loop ◽  
Cell Functions ◽  
Cytosolic Phospholipase ◽  
Signalling Cascades ◽  
Novel Strategy ◽  
G Protein Coupled

Lysophosphatidylinositol (LPI) is a well-known bioactive lipid that is able to activate signalling cascades relevant to cell proliferation, migration, survival and tumorigenesis. Our previous work suggested that LPI is involved in cancer progression since it can be released in the medium of Ras-transformed fibroblasts and can function as an autocrine modulator of cell growth. Different research groups have established that LPI is the specific and functional ligand for G-protein-coupled receptor 55 (GPR55) and that this GPR55–LPI axis is able to activate signalling cascades that are relevant for different cell functions. Work in our laboratory has recently unravelled an autocrine loop, by which LPI synthesized by cytosolic phospholipase A2 (cPLA2) is pumped out of the cell by ATP-binding cassette (ABC) transporter C1 (ABCC1)/multidrug resistance protein 1 (MRP1), initiating a signalling cascade downstream of GPR55. Our current work suggests that blockade of this pathway may represent a novel strategy to inhibit cancer cell proliferation.

scholarly journals Evidence for Osteocalcin Binding and Activation of GPRC6A in β-Cells

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1866-1880 ◽  
Author(s):  
Min Pi ◽  
Karan Kapoor ◽  
Ruisong Ye ◽  
Satoru Kenneth Nishimoto ◽  
Jeremy C. Smith ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Computational Models ◽  
Transmembrane Domain ◽  
Structural Basis ◽  
G Protein Coupled Receptor ◽  
Β Cells ◽  
Β Cell ◽  
Cell Functions ◽  
G Protein Coupled

Abstract The possibility that G protein-coupled receptor family C member A (GPRC6A) is the osteocalcin (Ocn)-sensing G protein-coupled receptor that directly regulates pancreatic β-cell functions is controversial. In the current study, we found that Ocn and an Ocn-derived C-terminal hexapeptide directly activate GPRC6A-dependent ERK signaling in vitro. Computational models probe the structural basis of Ocn binding to GPRC6A and predict that the C-terminal hexapeptide docks to the extracellular side of the transmembrane domain of GPRC6A. Consistent with the modeling, mutations in the computationally identified binding pocket of GPRC6A reduced Ocn and C-terminal hexapeptide activation of this receptor. In addition, selective deletion of Gprc6a in β-cells (Gprc6aβ-cell-cko) by crossing Gprc6aflox/flox mice with Ins2-Cre mice resulted in reduced pancreatic weight, islet number, insulin protein content, and insulin message expression. Both islet size and β-cell proliferation were reduced in Gprc6aβ-cell-cko compared with control mice. Gprc6aβ-cell-cko exhibited abnormal glucose tolerance, but normal insulin sensitivity. Islets isolated from Gprc6aβ-cell-cko mice showed reduced insulin simulation index in response to Ocn. These data establish the structural basis for Ocn direct activation of GPRC6A and confirm a role for GPRC6A in regulating β-cell proliferation and insulin secretion.

scholarly journals Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

2015 ◽  
Vol 112 (27) ◽  
pp. 8427-8432 ◽  
Author(s):  
Katja Spiess ◽  
Mads G. Jeppesen ◽  
Mikkel Malmgaard-Clausen ◽  
Karen Krzywkowski ◽  
Kalpana Dulal ◽  
...  
Keyword(s):  
G Protein ◽  
Pseudomonas Exotoxin ◽  
Viral Pathogen ◽  
Virus Origin ◽  
Ligand Interactions ◽  
Toxin Protein ◽  
Novel Strategy ◽  
G Protein Coupled

The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX3CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX3CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX3CL1, CX3CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo.

scholarly journals Regulating quantal size of neurotransmitter release through a GPCR voltage sensor

2020 ◽  
Vol 117 (43) ◽  
pp. 26985-26995 ◽  
Author(s):  
Quanfeng Zhang ◽  
Bing Liu ◽  
Yinglin Li ◽  
Lili Yin ◽  
Muhammad Younus ◽  
...  
Keyword(s):  
G Protein ◽  
Direct Interaction ◽  
Membrane Voltage ◽  
Dense Core Vesicle ◽  
Cell Functions ◽  
Quantal Size ◽  
Per Se ◽  
Adrenal Chromaffin ◽  
Myocyte Contractility ◽  
G Protein Coupled

Current models emphasize that membrane voltage (Vm) depolarization-induced Ca2+ influx triggers the fusion of vesicles to the plasma membrane. In sympathetic adrenal chromaffin cells, activation of a variety of G protein coupled receptors (GPCRs) can inhibit quantal size (QS) through the direct interaction of G protein Giβγ subunits with exocytosis fusion proteins. Here we report that, independently from Ca2+, Vm (action potential) per se regulates the amount of catecholamine released from each vesicle, the QS. The Vm regulation of QS was through ATP-activated GPCR-P2Y12 receptors. D76 and D127 in P2Y12 were the voltage-sensing sites. Finally, we revealed the relevance of the Vm dependence of QS for tuning autoinhibition and target cell functions. Together, membrane voltage per se increases the quantal size of dense-core vesicle release of catecholamine via Vm → P2Y12(D76/D127) → Giβγ → QS → myocyte contractility, offering a universal Vm-GPCR signaling pathway for its functions in the nervous system and other systems containing GPCRs.

scholarly journals G-Protein-Coupled Estrogen Receptor (GPER)-Specific Agonist G1 Induces ER Stress Leading to Cell Death in MCF-7 Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 503 ◽  
Author(s):  
Diep-Khanh Ho Vo ◽  
Roland Hartig ◽  
Sönke Weinert ◽  
Johannes Haybaeck ◽  
Norbert Nass
Keyword(s):  
Cell Death ◽  
Estrogen Receptor ◽  
Er Stress ◽  
G Protein ◽  
Cancer Progression ◽  
Cancer Cell Line ◽  
Positive Breast Cancer Cell ◽  
The Unfolded Protein Response ◽  
G Protein Coupled ◽  
Mcf 7

The G-protein-coupled estrogen receptor (GPER) mediates rapid non-genomic effects of estrogen. Although GPER is able to induce proliferation, it is down-regulated in breast, ovarian and colorectal cancer. During cancer progression, high expression levels of GPER are favorable for patients’ survival. The GPER-specific agonist G1 leads to an inhibition of cell proliferation and an elevated level of intracellular calcium (Ca2+). The purpose of this study is to elucidate the mechanism of G1-induced cell death by focusing on the connection between G1-induced Ca2+ depletion and endoplasmic reticulum (ER) stress in the estrogen receptor positive breast cancer cell line MCF-7. We found that G1-induced ER Ca2+ efflux led to the activation of the unfolded protein response (UPR), indicated by the phosphorylation of IRE1α and PERK and the cleavage of ATF6. The pro-survival UPR signaling was activated via up-regulation of the ER chaperon protein GRP78 and translational attenuation indicated by eIF2-α phosphorylation. However, the accompanying pro-death UPR signaling is profoundly activated and responsible for ER stress-induced cell death. Mechanistically, PERK-phosphorylation-induced JNK-phosphorylation and IRE1α-phosphorylation, which further triggered CAMKII-phosphorylation, are both implicated in G1-induced cell death. Our study indicates that loss of ER Ca2+ is responsible for G1-induced cell death via the pro-death UPR signaling.

Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation

Nature ◽  
1997 ◽  
Vol 385 (6614) ◽  
pp. 347-350 ◽  
Author(s):  
Leandros Arvanitakis ◽  
Elizabeth Geras-Raaka ◽  
Anjali Varma ◽  
Marvin C. Gershengorn ◽  
Ethel Cesarman
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Human Herpesvirus ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Constitutively Active

scholarly journals Leucine-rich repeat-containing G-protein-coupled receptor 8 in mature glomeruli of developing and adult rat kidney and inhibition by insulin-like peptide-3 of glomerular cell proliferation

2006 ◽  
Vol 189 (2) ◽  
pp. 397-408 ◽  
Author(s):  
P Fu ◽  
P-J Shen ◽  
C-X Zhao ◽  
D J Scott ◽  
C S Samuel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Binding Sites ◽  
Renal Cortex ◽  
Mesangial Cells ◽  
Rat Kidney ◽  
Leucine Rich Repeat ◽  
G Protein Coupled Receptor ◽  
Adult Rat ◽  
G Protein Coupled

Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8, or RXFP2) is a member of the type C leucine-rich repeat-containing G protein-coupled receptor family, and its endogenous ligand is insulin-like peptide-3 (INSL3). Although LGR8 expression has been demonstrated in various human tissues, including testis, ovary, brain and kidney, the precise roles of this receptor in many of these tissues are unknown. In an effort to better understand INSL3–LGR8 systems in the rat, we cloned the full-length Lgr8 cDNA and investigated the presence and cellular localization of Lgr8 mRNA expression in adult and developing rat kidney. On the basis of these findings, we investigated the presence and distribution of renal 125I-labelled human INSL3-binding sites and the nature of INSL3–LGR8 signalling in cultured renal cells. Thus, using in situ hybridization histochemistry, cells expressing Lgr8 mRNA were observed in glomeruli of renal cortex from adult rats and were tentatively identified as mesangial cells. Quantitative, real-time PCR analysis of the developmental profile of Lgr8 mRNA expression in kidney revealed highest relative levels at late stage gestation (embryonic day 18), with a sharp decrease after birth and lowest levels in the adult. During development, silver grains associated with Lgr8 mRNA hybridization were observed overlying putative mesangial cells in mature glomeruli, with little or no signal associated with less-mature glomeruli. In adult and developing kidney, specific 125I-INSL3-binding sites were associated with glomeruli throughout the renal cortex. In primary cultures of glomerular cells, synthetic human INSL3 specifically and dose-dependently inhibited cell proliferation over a 48 h period, further suggesting the presence of functional LGR8 (receptors) on these cells (mesangial and others). These findings suggest INSL3–LGR8 signalling may be involved in the genesis and/or developmental maturation of renal glomeruli and possibly in regulating mesangial cell density in adult rat kidney.

scholarly journals Urotensin II: an inflammatory cytokine

2019 ◽  
Vol 240 (3) ◽  
pp. R107-R117 ◽  
Author(s):  
Shui-lin Sun ◽  
Liang-ming Liu
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Tissue Distribution ◽  
G Protein ◽  
Inflammatory Cytokine ◽  
Animal Species ◽  
Inflammatory Diseases ◽  
The Body ◽  
Urotensin Ii ◽  
G Protein Coupled

Urotensin II (UII) is a polypeptide molecule with neurohormone-like activity. It has been confirmed that UII is widely distributed in numerous organs of different animal species from fish to mammals, including humans. The UII receptor is orphan G-protein-coupled receptor 14, also known as UT. The tissue distribution of UII and UT is highly consistent, and their expression may be regulated by autocrine and paracrine mechanisms. In the body, UII has many physiological and pathophysiological activities, such as vasoconstrictor and vasodilatory actions, cell proliferation, pro-fibrosis, neuroendocrine activity, insulin resistance and carcinogenic and inflammatory effects, which have been recognized only in recent years. In fact, UII is involved in the process of inflammatory injury and plays a key role in the onset and development of inflammatory diseases. In this paper, we will review the roles UII plays in inflammatory diseases.

scholarly journals Pharmacological Characterization of Veldoreotide as a Somatostatin Receptor 4 Agonist

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1075
Author(s):  
Pooja Dasgupta ◽  
Thomas Gűnther ◽  
Stefan Schulz
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Somatostatin Receptor ◽  
Somatostatin Receptors ◽  
Hek293 Cells ◽  
Somatostatin Analogue ◽  
Protein Signaling ◽  
Pharmacological Characterization ◽  
The Individual ◽  
G Protein Coupled

Veldoreotide, a somatostatin analogue, binds to the somatostatin receptors (SSTR) 2, 4, and 5. The current aim was to assess its pharmacological activity as an SSTR4 agonist. G-protein signaling was assessed using a fluorescence-based membrane potential assay in human embryonic kidney 293 (HEK293) cells stably co-expressing G-protein‒coupled inwardly rectifying potassium 2 channels and the individual SSTR2, SSTR4, and SSTR5, and in human BON-1 cells stably expressing these SSTRs. Veldoreotide effects on chromogranin A (CgA) secretion and cell proliferation were examined in BON-1 cells. In HEK293 transfected cells, veldoreotide showed a high efficacy for activating the SSTR4; octreotide and pasireotide had little activity (Emax, 99.5% vs. 27.4% and 52.0%, respectively). Veldoreotide also activated SSTR2 and SSTR5 (Emax, 98.4% and 96.9%, respectively). In BON-1 cells, veldoreotide activated SSTR2, SSTR4, and SSTR5 with high potency and efficacy. CgA secretion was decreased to a greater degree in the BON-1 cells expressing SSTR4 versus the cells expressing SSTR2 and SSTR5 (65.3% vs. 80.3% and 77.6%, respectively). In the BON-1 cells expressing SSTR4, veldoreotide inhibited cell proliferation more than somatostatin SS-14 (71.2% vs. 79.7%) and to a similar extent as the SSTR4 agonist J-2156 in the presence of SSTR2 and SSTR5 antagonists. Veldoreotide is a full agonist of SSTR2, SSTR4, and SSTR5.

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