Spatiotemporal control of cAMP signalling processes by anchored signalling complexes

2007 ◽  
Vol 35 (5) ◽  
pp. 931-937 ◽  
Author(s):  
E. Jarnæss ◽  
K. Taskén
Keyword(s):  
Biological Effects ◽  
G Protein Coupled Receptors ◽  
Scaffolding Proteins ◽  
Extracellular Signals ◽  
Temporal Specificity ◽  
Anchoring Proteins ◽  
Induced Changes ◽  
Pka Pathway ◽  
Spatiotemporal Control ◽  
G Protein Coupled

Ligand-induced changes in cAMP concentration vary in duration, amplitude and extension into the cell. cAMP microdomains are shaped by adenylate cyclases that form cAMP as well as PDEs (phosphodiesterases) that degrade cAMP. Various extracellular signals converge on the cAMP/PKA (protein kinase A) pathway through ligand binding to GPCRs (G-protein-coupled receptors) and the cAMP/PKA pathway is therefore tightly regulated on several levels to maintain specificity in the multitude of signal inputs. AKAPs (A-kinase-anchoring proteins) target PKA to specific substrates and distinct subcellular compartments, providing spatial and temporal specificity for mediation of biological effects channelled through the cAMP/PKA pathway. AKAPs also serve as scaffolding proteins that assemble PKA together with signal terminators such as phosphoprotein phosphatases and cAMP-specific PDEs as well as components of other signalling pathways into multiprotein signalling complexes.

scholarly journals Allosteric Modulation of GPCRs of Class A by Cholesterol

2021 ◽  
Vol 22 (4) ◽  
pp. 1953
Author(s):  
Jan Jakubík ◽  
Esam E. El-Fakahany
Keyword(s):  
Binding Sites ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Membrane Cholesterol ◽  
Extracellular Signals ◽  
High Affinity ◽  
Class A ◽  
Specific Effects ◽  
Induced Changes ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30% of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Additionally, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

scholarly journals Allosteric Modulation of GPCRs of Class A by Cholesterol

2021 ◽  
Author(s):  
Jan Jakubík ◽  
Esam E. El-Fakahany
Keyword(s):  
Binding Sites ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Membrane Cholesterol ◽  
Extracellular Signals ◽  
High Affinity ◽  
Class A ◽  
Specific Effects ◽  
Induced Changes ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30 % of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Also, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

scholarly journals Natural polyamines stimulate G-proteins

1992 ◽  
Vol 282 (2) ◽  
pp. 545-550 ◽  
Author(s):  
J L Bueb ◽  
A Da Silva ◽  
M Mousli ◽  
Y Landry
Keyword(s):  
Mast Cells ◽  
Pertussis Toxin ◽  
Inositol Phosphates ◽  
Second Messengers ◽  
G Protein Coupled Receptors ◽  
Extracellular Signals ◽  
Physiological Relevance ◽  
G Protein Coupled ◽  
Stimulation Of ◽  
Rat Mast Cells

The natural polyamines spermine and spermidine, the biosynthetic precursor putrescine and their analogues cadaverine and tyramine stimulate the GTPase activity of purified GTP-binding proteins (Go/Gi) from calf brain reconstituted into phospholipid vesicles. The order of potency was spermine greater than spermidine greater than putrescine = cadaverine greater than tyramine. The physiological relevance of this observation was assessed, showing the same order of potency of polyamines in the stimulation of peritoneal and tracheal rat mast cells. The activation of rat mast cells by polyamines was inhibited by benzalkonium chloride or by a 2 h pretreatment of the cells with pertussis toxin. The increase in inositol phosphates evoked by polyamines was also inhibited by pertussis toxin. Therefore we propose that intracellular polyamines might control the basal level of second messengers and modulate extracellular signals transduced through G-protein-coupled receptors.

scholarly journals Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

2007 ◽  
Vol 7 ◽  
pp. 1073-1081 ◽  
Author(s):  
Luigi F. Agnati ◽  
Giuseppina Leo ◽  
Susanna Genedani ◽  
Diego Guidolin ◽  
Nicola Andreoli ◽  
...  
Keyword(s):  
Immune System ◽  
G Protein ◽  
Cell Metabolism ◽  
G Protein Coupled Receptors ◽  
Host Cells ◽  
Receptor Function ◽  
Viral Receptor ◽  
Receptor Interactions ◽  
Induced Changes ◽  
G Protein Coupled

It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers), but clusters of receptors (receptor mosaics), altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

Energy and metabolic sensing G protein–coupled receptors during lactation-induced changes in energy balance

2014 ◽  
Vol 48 ◽  
pp. 33-41 ◽  
Author(s):  
P. Friedrichs ◽  
B. Saremi ◽  
S. Winand ◽  
J. Rehage ◽  
S. Dänicke ◽  
...  
Keyword(s):  
Energy Balance ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Metabolic Sensing ◽  
Induced Changes ◽  
G Protein Coupled

scholarly journals Fungal G-Protein-Coupled Receptors: A Promising Mediator of the Impact of Extracellular Signals on Biosynthesis of Ochratoxin A

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Gao ◽  
Xinge Xu ◽  
Kunlun Huang ◽  
Zhihong Liang
Keyword(s):  
G Protein ◽  
Ochratoxin A ◽  
G Protein Coupled Receptors ◽  
Aspergillus Ochraceus ◽  
Transmembrane Receptors ◽  
Environmental Signals ◽  
Extracellular Signals ◽  
Fungal Biology ◽  
The Impact ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are transmembrane receptors involved in transducing signals from the external environment inside the cell, which enables fungi to coordinate cell transport, metabolism, and growth to promote their survival, reproduction, and virulence. There are 14 classes of GPCRs in fungi involved in sensing various ligands. In this paper, the synthesis of mycotoxins that are GPCR-mediated is discussed with respect to ligands, environmental stimuli, and intra-/interspecific communication. Despite their apparent importance in fungal biology, very little is known about the role of ochratoxin A (OTA) biosynthesis by Aspergillus ochraceus and the ligands that are involved. Fortunately, increasing evidence shows that the GPCR that involves the AF/ST (sterigmatocystin) pathway in fungi belongs to the same genus. Therefore, we speculate that GPCRs play an important role in a variety of environmental signals and downstream pathways in OTA biosynthesis. The verification of this inference will result in a more controllable GPCR target for control of fungal contamination in the future.

scholarly journals II. Regulation of neuropeptide receptors in enteric neurons

1998 ◽  
Vol 274 (5) ◽  
pp. G792-G796
Author(s):  
Karen McConalogue ◽  
Nigel W. Bunnett
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Target Cell ◽  
Biological Effects ◽  
G Protein Coupled Receptors ◽  
Enteric Neurons ◽  
Heterotrimeric G Proteins ◽  
High Affinity ◽  
Neuropeptide Receptors ◽  
G Protein Coupled

Neuropeptides exert their diverse biological effects by interacting with G protein-coupled receptors (GPCRs). In this review we address the question, What regulates the ability of a target cell, in particular a neuron, to respond to a neuropeptide? Available evidence from studies of many GPCRs in reconstituted systems and transfected cell lines indicates that much of this regulation occurs at the level of the receptor and serves to alter the capacity of the receptor to bind ligands with high affinity and to couple to heterotrimeric G proteins. Although some of the knowledge gained from these studies is applicable to the regulation of neuropeptide receptors on neurons, at present there are far more questions than answers.

scholarly journals AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes

2004 ◽  
Vol 379 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Craig C. MALBON ◽  
Jiangchuan TAO ◽  
Hsien-yu WANG
Keyword(s):  
G Protein ◽  
Tyrosine Kinases ◽  
Cell Signalling ◽  
G Protein Coupled Receptors ◽  
Dynamic Regulation ◽  
Receptor Signalling ◽  
Anchoring Proteins ◽  
Β2 Adrenergic Receptor ◽  
Cytoskeletal Elements ◽  
G Protein Coupled

Cell signalling mediated via GPCRs (G-protein-coupled receptors) is a major paradigm in biology, involving the assembly of receptors, G-proteins, effectors and downstream elements into complexes that approach in design ‘solid-state’ signalling devices. Scaffold molecules, such as the AKAPs (A-kinase anchoring proteins), were discovered more than a decade ago and represent dynamic platforms, enabling multivalent signalling. AKAP79 and AKAP250 were the first to be shown to bind to membrane-embedded GPCRs, orchestrating the interactions of various protein kinases (including tyrosine kinases), protein phosphatases (e.g. calcineurin) and cytoskeletal elements with at least one member of the superfamily of GPCRs, the prototypical β2-adrenergic receptor. In this review, the multivalent interactions of AKAP250 with the cell membrane, receptor, cytoskeleton and constituent components are detailed, providing a working model for AKAP-based GPCR signalling complexes. Dynamic regulation of the AKAP–receptor complex is mediated by ordered protein phosphorylation.

scholarly journals Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anja Floeser ◽  
Katharina Becker ◽  
Evi Kostenis ◽  
Gabriele König ◽  
Cornelius Krasel ◽  
...  
Keyword(s):  
G Protein ◽  
Acetylcholine Receptor ◽  
Rank Order ◽  
Muscarinic Acetylcholine Receptor ◽  
G Protein Coupled Receptors ◽  
Effector Proteins ◽  
Muscarinic Acetylcholine ◽  
Extracellular Signals ◽  
G Protein Coupled ◽  
Different Levels

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses – termed bias – potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct.

scholarly journals The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders

2019 ◽  
Vol 20 (14) ◽  
pp. 3580 ◽  
Author(s):  
Airi Jo-Watanabe ◽  
Toshiaki Okuno ◽  
Takehiko Yokomizo
Keyword(s):  
Biological Effects ◽  
Expression Patterns ◽  
Allergic Diseases ◽  
G Protein Coupled Receptors ◽  
Receptor Subtype ◽  
Recent Developments ◽  
Acute And Chronic Inflammation ◽  
Allergic Disorders ◽  
G Protein Coupled

Leukotrienes (LTs) are lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases. They exert their biological effects by binding to specific G-protein-coupled receptors. Each LT receptor subtype exhibits unique functions and expression patterns. LTs play roles in various allergic diseases, including asthma (neutrophilic asthma and aspirin-sensitive asthma), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and anaphylaxis. This review summarizes the biology of LTs and their receptors, recent developments in the area of anti-LT strategies (in settings such as ongoing clinical studies), and prospects for future therapeutic applications.

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