Identification of the C3a Receptor (C3AR1) as the Target of the VGF-derived Peptide TLQP-21 in Rodent Cells

TLQP-21, a peptide derived from VGF (non-acronymic) by proteolytic processing, has been shown to modulate energy metabolism, differentiation, and cellular response to stress. Although extensively investigated, the receptor for this endogenous peptide has not previously been described. This study describes the use of a series of studies that show G protein-coupled receptor-mediated biological activity of TLQP-21 signaling in CHO-K1 cells. Unbiased genome-wide sequencing of the transcriptome from responsive CHO-K1 cells identified a prioritized list of possible G protein-coupled receptors bringing about this activity. Further experiments using a series of defined receptor antagonists and siRNAs led to the identification of complement C3a receptor-1 (C3AR1) as a target for TLQP-21 in rodents. We have not been able to demonstrate so far that this finding is translatable to the human receptor. Our results are in line with a large number of physiological observations in rodent models of food intake and metabolic control, where TLQP-21 shows activity. In addition, the sensitivity of TLQP-21 signaling to pertussis toxin is consistent with the known signaling pathway of C3AR1. The binding of TLQP-21 to C3AR1 not only has effects on signaling but also modulates cellular functions, as TLQP-21 was shown to have a role in directing migration of mouse RAW264.7 cells.

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Genome-wide profiling of G protein-coupled receptors in cerebellar granule neurons using high-throughput, real-time PCR

BMC Genomics ◽

10.1186/1471-2164-12-241 ◽

2011 ◽

Vol 12 (1) ◽

Cited By ~ 4

Author(s):

Benjamin Maurel ◽

Anne Le Digarcher ◽

Christelle Dantec ◽

Laurent Journot

Keyword(s):

Real Time ◽

G Protein ◽

High Throughput ◽

Real Time Pcr ◽

G Protein Coupled Receptors ◽

Cerebellar Granule Neurons ◽

Granule Neurons ◽

Cerebellar Granule ◽

Genome Wide ◽

G Protein Coupled

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Genome-wide prediction and comparative transcriptomic analysis reveals the G protein-coupled receptors involved in gonadal development of Apostichopus japonicus

Genomics ◽

10.1016/j.ygeno.2020.10.030 ◽

2020 ◽

Author(s):

Dexiang Huang ◽

Bing Zhang ◽

Tao Han ◽

Guangbin Liu ◽

Xu Chen ◽

...

Keyword(s):

G Protein ◽

Apostichopus Japonicus ◽

Gonadal Development ◽

G Protein Coupled Receptors ◽

Transcriptomic Analysis ◽

Genome Wide ◽

G Protein Coupled ◽

Comparative Transcriptomic Analysis

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Atypical Chemokine Receptors in Cardiovascular Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1676988 ◽

2019 ◽

Vol 119 (04) ◽

pp. 534-541 ◽

Cited By ~ 4

Author(s):

Selin Gencer ◽

Emiel van der Vorst ◽

Maria Aslani ◽

Christian Weber ◽

Yvonne Döring ◽

...

Keyword(s):

G Protein ◽

Chemokine Receptors ◽

Cellular Response ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Signalling Pathways ◽

Atherosclerosis Development ◽

G Protein Coupled ◽

Precise Role

AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.

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ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors

AJP Cell Physiology ◽

10.1152/ajpcell.00620.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. C1-C10 ◽

Cited By ~ 235

Author(s):

Haruhiko Ohtsu ◽

Peter J. Dempsey ◽

Satoru Eguchi

Keyword(s):

G Protein ◽

Egf Receptor ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Surface Proteins ◽

Egf Receptors ◽

Cellular Functions ◽

Egfr Transactivation ◽

And Migration ◽

G Protein Coupled

A disintegrin and metalloprotease (ADAM) is a membrane-anchored metalloprotease implicated in the ectodomain shedding of cell surface proteins, including the ligands for epidermal growth factor (EGF) receptors (EGFR)/ErbB. It has been well documented that the transactivation of the EGFR plays critical roles for many cellular functions, such as proliferation and migration mediated through multiple G protein-coupled receptors (GPCRs). Recent accumulating evidence has suggested that ADAMs are the key metalloproteases activated by several GPCR agonists to produce a mature EGFR ligand leading to the EGFR transactivation. In this review, we describe the current knowledge on ADAMs implicated in mediating EGFR transactivation. The major focus of the review will be on the possible upstream mechanisms of ADAM activation by GPCRs as well as downstream signal transduction and the pathophysiological significances of ADAM-dependent EGFR transactivation.

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Organized cannabinoid receptor distribution in neurons revealed by super-resolution fluorescence imaging

Nature Communications ◽

10.1038/s41467-020-19510-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Hui Li ◽

Jie Yang ◽

Cuiping Tian ◽

Min Diao ◽

Quan Wang ◽

...

Keyword(s):

G Protein ◽

Fluorescence Imaging ◽

Cannabinoid Receptor ◽

Super Resolution ◽

G Protein Coupled Receptors ◽

Cellular Functions ◽

Cannabinoid Receptor 1 ◽

Intracellular Organization ◽

Dynamic Movement ◽

G Protein Coupled

Abstract G-protein-coupled receptors (GPCRs) play important roles in cellular functions. However, their intracellular organization is largely unknown. Through investigation of the cannabinoid receptor 1 (CB1), we discovered periodically repeating clusters of CB1 hotspots within the axons of neurons. We observed these CB1 hotspots interact with the membrane-associated periodic skeleton (MPS) forming a complex crucial in the regulation of CB1 signaling. Furthermore, we found that CB1 hotspot periodicity increased upon CB1 agonist application, and these activated CB1 displayed less dynamic movement compared to non-activated CB1. Our results suggest that CB1 forms periodic hotspots organized by the MPS as a mechanism to increase signaling efficacy upon activation.

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The mouse cytomegalovirus G protein-coupled receptor homolog, M33, coordinates key features of in vivo infection via distinct components of its signalling repertoire.

Journal of Virology ◽

10.1128/jvi.01867-21 ◽

2021 ◽

Author(s):

Jiawei Ma ◽

Kimberley Bruce ◽

Nicholas Davis-Poynter ◽

Philip G Stevenson ◽

Helen E. Farrell

Keyword(s):

G Protein ◽

Cellular Response ◽

G Protein Coupled Receptors ◽

Viral Fitness ◽

Mouse Cytomegalovirus ◽

High Endothelial Venules ◽

Targeted Interventions ◽

Key Features ◽

G Protein Coupled

Common to all cytomegalovirus (CMV) genomes analysed to date is the presence of G protein-coupled receptors (GPCR). Animal models of CMV provide insights into their role in viral fitness. The mouse cytomegalovirus (MCMV) GPCR, M33, facilitates dendritic cell (DC)-dependent viremia, the extravasation of blood-borne infected DC to the salivary gland and the frequency of reactivation events from latently-infected tissue explants. Constitutive G protein-coupled M33 signalling is required for these phenotypes, although the contribution of distinct biochemical pathways activated by M33 is unknown. M33 engages G q/11 to constitutively activate phospholipase C β (PLCβ) and downstream cyclic AMP response-element binding protein (CREB) in vitro . Identification of a MCMV M33 mutant (M33 ΔC38 ) for which CREB signalling was disabled, but PLCβ activation was preserved, provided the opportunity to investigate their relevance in vivo . Following intranasal infection with MCMV M33 ΔC38 , the absence of M33 CREB G q/11 -dependent signalling correlated with reduced mobilisation of lytically-infected DC to draining lymph node high endothelial venules (HEVs) and reduced viremia compared with wild type MCMV. In contrast, M33 ΔC38 -infected DC within the vascular compartment extravasated to the salivary glands via a pertussis toxin-sensitive, G i/o -dependent and CREB-independent mechanism. In the context of MCMV latency, spleen explants from M33 ΔC38 -infected mice were markedly attenuated for reactivation. Taken together, these data demonstrate that key features of the MCMV lifecycle are coordinated in diverse tissues by distinct pathways of the M33 signalling repertoire. IMPORTANCE G protein-coupled receptors (GPCRs) act as cell surface molecular “switches” which regulate the cellular response to environmental stimuli. All cytomegalovirus (CMV) genomes analysed to date possess GPCR homologs with phylogenetic evidence for independent gene capture events, signifying important in vivo roles. The mouse CMV (MCMV) GPCR homolog, designated M33, is important for cell-associated virus spread and for the establishment and/or reactivation of latent MCMV infection. The signalling repertoire of M33 is distinct from cellular GPCRs and little is known of the relevance of component signalling pathways for in vivo M33 function. In this report, we show temporal and tissue-specific M33 signalling is required facilitating in vivo infection. Understanding the relevance of the viral GPCR signalling profiles for in vivo function will provide opportunities for future targeted interventions.

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Ubiquitination Regulates Proteolytic Processing of G Protein-coupled Receptors after Their Sorting to Lysosomes

Journal of Biological Chemistry ◽

10.1074/jbc.m109.001644 ◽

2009 ◽

Vol 284 (29) ◽

pp. 19361-19370 ◽

Cited By ~ 60

Author(s):

James N. Hislop ◽

Anastasia G. Henry ◽

Adriano Marchese ◽

Mark von Zastrow

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Proteolytic Processing ◽

G Protein Coupled

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G protein co-signaling and challenges for translational research

Translational Neuroscience ◽

10.2478/s13380-013-0102-9 ◽

2013 ◽

Vol 4 (1) ◽

Cited By ~ 3

Author(s):

Irene Litosch

Keyword(s):

G Protein ◽

Cellular Response ◽

Oscillatory Behavior ◽

G Protein Coupled Receptors ◽

Inositol 1 ◽

Kinase C ◽

Multiple Levels ◽

High Concentrations ◽

G Protein Coupled ◽

Self Organizing

AbstractThe Gq-linked G protein coupled receptors (GPCRs) and their signaling pathways are important clinical targets for the dementia of Alzheimer’s disease and cognitive decline with aging. Gq stimulates phospholipase C-β1 (PLC-β1) activity, increasing levels of inositol-1, 4, 5-trisphosphate (IP3) and diacylglycerol, to initiate mobilization of intracellular Ca2+ and activation of protein kinase C, respectively. While high concentrations of ligand typically evoke large sustained increases in cytosolic Ca2+ levels, it has long been appreciated that the dynamics of the Ca2+ increase are more complex and consistent with multiple levels of regulation. Physiologically relevant concentrations of Gq-ligands evoke rhythmic fluctuations or an oscillation in the level of cytosolic Ca2+. Downstream targets are tuned to respond to the frequency of the Ca2+ oscillations which in turn, reflect the oscillations in IP3 levels. Oscillatory behavior depends on the assembly of self-organizing interactions. The components that contribute to and regulate the Ca2+ oscillator have been unclear, precluding transfer of this fundamental knowledge from bench to bedside. Many GPCRs that signal with Gq also co-signal with G12. G protein co-signaling could therefore regulate the Ca2+ oscillator. This letter explores the potential relationship between Ca2+ oscillations, G protein co-signaling and cellular response in the context of our recent observations. We found that Gq efficacy is synergistic with phosphatidic acid, (PA), a signaling mediator generated downstream of activated G12 and RhoA. Regulation by PA depends on interaction with the unique PLC-β1 PA binding region. G protein co-signaling is therefore a mechanism for GPCRs to collectively assemble self-organizing interactions that regulate the Ca2+ oscillator.

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