scholarly journals A single receptor encoded by vzg-1/lpA1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophosphatidic acid

1998 ◽  
Vol 95 (11) ◽  
pp. 6151-6156 ◽  
Author(s):  
N. Fukushima ◽  
Y. Kimura ◽  
J. Chun
Keyword(s):  
G Proteins ◽  
Lysophosphatidic Acid ◽  
Cellular Responses ◽  
Single Receptor

Multifunctional G Proteins: Implication in Endotoxin Cellular Responses

2020 ◽  
pp. 537-547
Author(s):  
Lawrence P. Fernando ◽  
Michel A. Makhlouf ◽  
J. A. Cook
Keyword(s):  
G Proteins ◽  
Cellular Responses

scholarly journals Physiology of the orexinergic/hypocretinergic system: a revisit in 2012

2013 ◽  
Vol 304 (1) ◽  
pp. C2-C32 ◽  
Author(s):  
Jyrki P. Kukkonen
Keyword(s):  
Central Nervous System ◽  
G Proteins ◽  
Cellular Responses ◽  
G Protein Coupled Receptors ◽  
Heterotrimeric G Proteins ◽  
Neuronal Excitation ◽  
System A ◽  
The Central Nervous System ◽  
G Protein Coupled ◽  
Systemic Responses

The neuropeptides orexins and their G protein-coupled receptors, OX1and OX2, were discovered in 1998, and since then, their role has been investigated in many functions mediated by the central nervous system, including sleep and wakefulness, appetite/metabolism, stress response, reward/addiction, and analgesia. Orexins also have peripheral actions of less clear physiological significance still. Cellular responses to the orexin receptor activity are highly diverse. The receptors couple to at least three families of heterotrimeric G proteins and other proteins that ultimately regulate entities such as phospholipases and kinases, which impact on neuronal excitation, synaptic plasticity, and cell death. This article is a 10-year update of my previous review on the physiology of the orexinergic/hypocretinergic system. I seek to provide a comprehensive update of orexin physiology that spans from the molecular players in orexin receptor signaling to the systemic responses yet emphasizing the cellular physiological aspects of this system.

scholarly journals Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

1997 ◽  
Vol 322 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Stephan K. BÖHM ◽  
Eileen F. GRADY ◽  
Nigel W. BUNNETT
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Extracellular Fluid ◽  
Cellular Responses ◽  
Drug Tolerance ◽  
G Protein Coupled Receptors ◽  
Regulatory Mechanisms ◽  
Receptor Desensitization ◽  
Down Regulation ◽  
G Protein Coupled

The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and down-regulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from G-proteins. Agonist-induced receptor endocytosis also contributes to desensitization by depleting the cell surface of high-affinity receptors, and recycling of internalized receptors contributes to resensitization of cellular responses. Receptor down-regulation is a form of desensitization that occurs during continuous, long-term exposure of cells to receptor agonists. Down-regulation, which may occur during the development of drug tolerance, is characterized by depletion of the cellular receptor content, and is probably mediated by alterations in the rates of receptor degradation and synthesis. These regulatory mechanisms are important, as they govern the ability of cells to respond to agonists. A greater understanding of the mechanisms that modulate signalling may lead to the development of new therapies and may help to explain the mechanism of drug tolerance.

Cellular signaling responses mediated by a novel nucleotide receptor in rabbit microvessel endothelium

1993 ◽  
Vol 265 (2) ◽  
pp. H675-H680
Author(s):  
R. J. Mannix ◽  
T. Moatter ◽  
K. A. Kelley ◽  
M. E. Gerritsen
Keyword(s):  
Endothelial Cells ◽  
Cardiac Muscle ◽  
Inositol Phosphate ◽  
Adenine Nucleotide ◽  
Rank Order ◽  
Cellular Signaling ◽  
Cellular Responses ◽  
Pyrimidine Nucleotides ◽  
Single Receptor ◽  
Prostaglandin Release

The adenine nucleotide, ATP, elicits an elevation in intracellular ionized calcium concentration ([Ca2+]i) and phospholipase C-mediated phosphatidylinositol hydrolysis and stimulates the synthesis of the prostaglandins E2 and I2 in cultured endothelial cells derived from rabbit cardiac muscle. Use of various ATP analogues indicated that these events did not fit the classical definition of P1 or P2 purinergic receptors and, furthermore, indicated that the receptor(s) mediating these activities was not specific for purines. The rank order of agonist potency on prostaglandin release, elevations in [Ca2+]i, and inositol phosphate response was UTP > or = ATP > ADP > ADP[beta]S = 2-methylthio ATP > adenosine, suggesting that these three cellular responses are coupled to the same or similar receptors. However, the sensitivity of these three cellular responses to added nucleotides was somewhat different. The half-maximum effective concentration (EC50) for ATP stimulation of prostaglandin release was 100 microM, for inositol phosphate turnover it was 25 microM, and for elevations in [Ca2+]i it was < 1 microM. Similar discrepancies in EC50 UTP values for these three cellular responses were also noted. These observations indicate that purine and pyrimidine nucleotides elicit at least three cellular responses in rabbit cardiac muscle microvessel endothelial cells, all demonstrating similar rank orders of potency. However, the differences in EC50 suggest that if these responses are mediated by a single receptor type, it exhibits divergent coupling to various cellular signaling pathways.

Computational Methods for the Prediction of GPCRs Coupling Selectivity

2009 ◽  
pp. 167-181
Author(s):  
Nikolaos G. Sgourakis ◽  
Pantelis G. Bagos ◽  
Stavros J. Hamodrakas
Keyword(s):  
G Proteins ◽  
Drug Targets ◽  
Large Scale ◽  
Single Receptor ◽  
Pharmacological Significance ◽  
Experimental Works ◽  
Orphan Gpcrs ◽  
Coupling Specificity ◽  
Novel Drug ◽  
Genome Projects

GPCRs comprise a wide and diverse class of eukaryotic transmembrane proteins with well-established pharmacological significance. As a consequence of recent genome projects, there is a wealth of information at the sequence level that lacks any functional annotation. These receptors, often quoted as orphan GPCRs, could potentially lead to novel drug targets. However, typical experiments that aim at elucidating their function are hampered by the lack of knowledge on their selective coupling partners at the interior of the cell, the G-proteins. Up-to-date, computational efforts to predict properties of GPCRs have been focused mainly on the ligand-binding specificity, while the aspect of coupling has been less studied. Here, we present the main motivations, drawbacks, and results from the application of bioinformatics techniques to predict the coupling specificity of GPCRs to G-proteins, and discuss the application of the most successful methods in both experimental works that focus on a single receptor and large-scale genome annotation studies.

scholarly journals Lysophosphatidic acid attenuates the cytotoxic effects and degree of peroxisome proliferator-activated receptor γ activation induced by 15-deoxyΔ12,14-prostaglandin J2 in neuroblastoma cells

2004 ◽  
Vol 382 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Helen A. RODWAY ◽  
Alan N. HUNT ◽  
Janice A. KOHLER ◽  
Anthony D. POSTLE ◽  
Karen A. LILLYCROP
Keyword(s):  
Cell Death ◽  
Growth Inhibition ◽  
Lysophosphatidic Acid ◽  
Serum Lipid ◽  
Neuroblastoma Cells ◽  
Cellular Responses ◽  
Complete Medium ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Phosphoinositide 3 Kinase

PPARγ (peroxisome proliferator-activated receptor γ) is a ligand-activated transcription factor that responds to 15dPGJ2 (15-deoxy-Δ12,14-prostglandin J2). 15dPGJ2, in vitro, halts neuroblastoma cell growth, but reported mechanisms vary. Here we evaluated the modulatory effects of endogenous serum lipid mitogens upon the extent of 15dPGJ2-induced growth inhibition and on the precise cellular responses of neuroblastoma cells to PPARγ activation. We show that 15dPGJ2 specifically inhibited cell growth in both complete and delipidated media. 15dPGJ2-induced growth inhibition was accompanied by decreased cell viability, although the effect was far more marked in delipidated medium than in complete medium. Incubation with 15dPGJ2 in complete medium resulted in cytoplasmic changes characteristic of type II programmed cell death (autophagy), while prior serum lipid removal resulted in cell death via an apoptotic mechanism. These distinct, serum lipid-dependent cellular responses to 15dPGJ2 were accompanied by increases in the expression of a reporter gene construct containing a PPAR response element of 2.3-fold in complete medium, but of 4.8-fold in delipidated medium. Restoration of the serum lysolipid LPA (lysophosphatidic acid) to cells in delipidated medium reduced 15dPGJ2-mediated PPARγ activation, growth inhibition and cell death; following addition of S1P (sphingosine 1-phosphate), decreases were apparent but more marginal. Further, while the effects of LPA in delipidated medium were mediated through a Gi/phosphoinositide 3-kinase/MAPK (mitogen-activated protein kinase) pathway, those of S1P did not involve the MAPK component. These data suggest that the serum lysolipid LPA modulates the degree of PPARγ activation and the precise cellular response to 15dPGJ2 via activation of a Gi/phosphoinositide 3-kinase/MAPK pathway.

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