G protein co-signaling and challenges for translational research

2013 ◽  
Vol 4 (1) ◽  
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.

scholarly journals Atypical Chemokine Receptors in Cardiovascular Disease

2019 ◽  
Vol 119 (04) ◽  
pp. 534-541 ◽  
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.

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

2013 ◽  
Vol 288 (38) ◽  
pp. 27434-27443 ◽  
Author(s):  
Sebastien Hannedouche ◽  
Valerie Beck ◽  
Juliet Leighton-Davies ◽  
Martin Beibel ◽  
Guglielmo Roma ◽  
...  
Keyword(s):  
G Protein ◽  
Cellular Response ◽  
G Protein Coupled Receptors ◽  
Proteolytic Processing ◽  
Rodent Models ◽  
Cellular Functions ◽  
Genome Wide ◽  
Response To Stress ◽  
G Protein Coupled ◽  
Human Receptor

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.

G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors

10.1038/7243 ◽  
1999 ◽  
Vol 2 (4) ◽  
pp. 331-338 ◽  
Author(s):  
W-Y. Lu ◽  
Z-G. Xiong ◽  
S. Lei ◽  
B. A. Orser ◽  
E. Dudek ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Nmda Receptors ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Kinase C ◽  
G Protein Coupled

Alignment-Free Classification of G-Protein-Coupled Receptors Using Self-Organizing Maps

2006 ◽  
Vol 46 (3) ◽  
pp. 1479-1490 ◽  
Author(s):  
Joji M. Otaki ◽  
Akihito Mori ◽  
Yoshimasa Itoh ◽  
Takashi Nakayama ◽  
Haruhiko Yamamoto
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Self Organizing Maps ◽  
Alignment Free ◽  
Free Classification ◽  
G Protein Coupled ◽  
Self Organizing

scholarly journals Role of Protein Kinase C, PI3-kinase and Tyrosine Kinase in Activation of MAP Kinase by Glucose and Agonists of G-protein Coupled Receptors in INS-1 Cells

2001 ◽  
Vol 2 (3) ◽  
pp. 233-244 ◽  
Author(s):  
Dietmar Böcker ◽  
Eugen J. Verspohl
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Map Kinase ◽  
G Protein ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Pi3 Kinase ◽  
G Protein Coupled Receptors ◽  
Kinase C ◽  
G Protein Coupled

MAP (mitogen-activated protein) kinase (also called Erk 1/2) plays a crucial role in cell proliferation and differentiation. Its impact on secretory events is less well established. The interplay of protein kinase C (PKC), PI3-kinase nd cellular tyrosine kinase with MAP kinase activity using inhibitors and compounds such as glucose, phorbol 12-myristate 13-acetate (PMA) and agonists of G-protein coupled receptors like gastrin releasing peptide (GRP), oxytocin (OT) and glucose-dependent insulinotropic peptide (GIP) was investigated in INS-1 cells, an insulin secreting cell line. MAP kinase activity was determined by using a peptide derived from the EGF receptor as a MAP kinase substrate and [P32]ATP. Glucose as well as GRP, OT and GIP exhibited a time-dependent increase in MAP kinase activity with a maximum at time point 2.5 min. All further experiments were performed using 2.5 min incubations. The flavone PD 098059 is known to bind to the inactive forms of MEK1 (MAPK/ERK-Kinase) thus preventing activation by upstream activators. 20 μM PD 098059 (IC50=51 μM) inhibited MAP kinase stimulated by either glucose, GRP, OT, GIP or PMA. Inhibiton (“downregulation”) of PKC by a long term (22h) pretreatment with 1 μM PMA did not influence MAP kinase activity when augmented by either of the above mentioned compound. To investigate whether PI3-kinase and cellular tyrosine kinase are involved in G-protein mediated effects on MAP kinase, inhibitors were used: 100 nM wortmannin (PI3-kinase inhibitor) reduced the effects of GRP, OT and GIP but not that of PMA; 100 μM genistein (tyrosine kinase inhibitor) inhibited the stimulatory effect of either above mentioned compound on MAP kinase activation. Inhibition of MAP kinase by 20 μM PD 098059 did not influence insulin secretion modulated by either compound (glucose, GRP, OT or GIP). [H3]Thymidine incorporation, however, was severely inhibited by PD 098059. Thus MAP kinase is important for INS-1 cell proliferation but not for its insulin secretory response with respect to major initiators and modulators of insulin release. The data indicate that MAP kinase is active and under the control of MAP kinase. PKC is upstream of a genisteinsensitive tyrosine kinase and probably downstream of a PI3-kinase in INS-1 cells.

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

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.

Multiple Signaling Pathways for Platelet-Activating Factor Receptor

Physiology ◽  
1992 ◽  
Vol 7 (2) ◽  
pp. 72-75
Author(s):  
SD Shukla
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
G Protein ◽  
Platelet Activating Factor ◽  
G Protein Coupled Receptors ◽  
Kinase C ◽  
Paf Receptor ◽  
Multiple Signaling ◽  
G Protein Coupled

Platelet-activating factor (PAF) receptor is coupled to multiple signaling pathways, including phospholipid turnover via phospholipases C, D, A2;Ca2+ mobilization;and activation of protein kinase C and tyrosine kinase. The cloned receptor shows homology to G protein-coupled receptors. These developments highlight receptor functions of this novel phospholipid agonist.

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