scholarly journals Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 785 ◽  
Author(s):  
Wiwin Is Effendi ◽  
Tatsuya Nagano ◽  
Kazuyuki Kobayashi ◽  
Yoshihiro Nishimura
Keyword(s):  
G Proteins ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Signal Pathway ◽  
Human Diseases ◽  
Therapeutic Drug ◽  
Drug Candidates ◽  
Biological Features ◽  
Partial Agonists ◽  
Membrane Bound

Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A1AR, A2AAR, A2BAR, and A3AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A1AR and A2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A2BAR and A3AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases.

scholarly journals Interactions of purified bovine brain A1-adenosine receptors with G-proteins. Reciprocal modulation of agonist and antagonist binding

1991 ◽  
Vol 275 (3) ◽  
pp. 651-656 ◽  
Author(s):  
M Freissmuth ◽  
E Selzer ◽  
W Schütz
Keyword(s):  
G Proteins ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Bovine Brain ◽  
Detergent Solution ◽  
Maximal Effect ◽  
A1 Adenosine Receptor ◽  
Molar Excess ◽  
A1 Adenosine Receptors ◽  
Antagonist Binding

The bovine brain A1-adenosine receptor was purified 8000-fold by affinity chromatography on xanthine-amine-congener (XAC)-Sepharose. Addition of a 120-fold molar excess of a purified bovine brain G-protein preparation (Go,i a mixture of Go and Gi, containing predominantly Go) decreases the Bmax of the binding of the antagonist radioligand [3H]XAC to the receptor. This decrease is observed not only after insertion into phospholipid vesicles but also in detergent solution, and is reversed by GTP analogues. In the presence of Go,i, about 20 and 40% of the receptors display guanine-nucleotide-sensitive high-affinity binding of the agonist radioligand (-)-N6-3-([125I]iodo-4-hydroxyphenylisopropyl)adenosine after reconstitution into lipid vesicles and in detergent solution, respectively. The ability of Go,i to enhance agonist binding and decrease antagonist binding is concentration-dependent, with a half-maximal effect occurring at approximately 10-fold molar excess of G-proteins over A1-adenosine receptors. In the presence of the receptor, the rate of guanosine 5′-[gamma-[35S]thio]triphosphate (GTP[35S]) binding to Go,i is accelerated. This rate is further enhanced if the receptor is activated by the agonist (-)(R)-N6-phenylisopropyladenosine, whereas the antagonist XAC decreases the association rate of GTP[35S] to levels observed in the absence of receptor. These results show (1) that detergent removal is not a prerequisite for the observation of coupling between the A1-adenosine receptor and Go,i, and (2) that the regulatory effect of G-proteins on antagonist binding to the A1-adenosine receptor can be reconstituted by using purified components.

Cardiac desensitization to adenosine analogues after prolonged R-PIA infusion in vivo

1993 ◽  
Vol 265 (6) ◽  
pp. H1916-H1927 ◽  
Author(s):  
H. T. Lee ◽  
C. I. Thompson ◽  
A. Hernandez ◽  
J. L. Lewy ◽  
F. L. Belloni
Keyword(s):  
G Proteins ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Radioligand Binding ◽  
Significant Loss ◽  
Binding Assays ◽  
Adenosine Receptor Agonists ◽  
Receptor Agonists ◽  
A1 Receptor

To determine the effects of chronic in vivo stimulation of adenosine receptors, R-(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), a selective A1 receptor agonist, was administered to rats as a continuous 7-day infusion (200 nmol/h). Inotropic and chronotropic responses of isolated atria to adenosine receptor agonists were markedly desensitized compared with the responses of atria from age-matched control animals. Carbachol's negative chronotropic effect was also attenuated, indicating a heterologous mode of desensitization. Antagonist radioligand binding assays indicated a 52% reduction in A1 adenosine receptor maximum binding, and competition binding assays revealed a significant loss of G protein-coupled high-affinity A1 receptors in atria from R-PIA-treated rats. Inhibitory G proteins (Gi) were significantly reduced, as quantified by immunoblot analysis, with no change in the amount of stimulatory G proteins. Ventricular membranes from R-PIA rats showed loss of Gi and uncoupling of A1 receptors, without a significant change in A1 receptor density. Thus chronic R-PIA infusion desensitized rat atrial muscle to the effects of adenosine receptor agonists via several regulatory adaptations, including downregulation of A1 adenosine receptors, uncoupling of A1 receptors from their associated G proteins, and loss of Gi proteins.

Exosome: An Emerging Source of Biomarkers for Human Diseases

2019 ◽  
Vol 19 (6) ◽  
pp. 387-394 ◽  
Author(s):  
Li Xu ◽  
Long-Fei Wu ◽  
Fei-Yan Deng
Keyword(s):  
Breast Milk ◽  
Intercellular Communication ◽  
Translational Medicine ◽  
Disease Diagnosis ◽  
Human Diseases ◽  
Isolation And Identification ◽  
Biomarker Identification ◽  
Biological Features ◽  
Diagnosis And Prognosis ◽  
Novel Biomarkers

Exosomes are 30-120nm long endocytic membrane-derived vesicles, which are secreted by various types of cells and stably present in body fluids, such as plasma, urine, saliva and breast milk. Exosomes participate in intercellular communication. Recently accumulative studies have suggested that exosomes may serve as novel biomarkers for disease diagnosis and prognosis. Herein, we reviewed the biological features of exosomes, technologies for exosome isolation and identification, as well as progress in exosomal biomarker identification, highlighting the relevance of exosome to human diseases and significance and great potential in translational medicine.

The heterotrimeric Gi(3) protein acts in slow but not in fast exocytosis of rat melanotrophs

1999 ◽  
Vol 112 (22) ◽  
pp. 4143-4150 ◽  
Author(s):  
M. Kreft ◽  
S. Gasman ◽  
S. Chasserot-Golaz ◽  
V. Kuster ◽  
M. Rupnik ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
G Proteins ◽  
Flash Photolysis ◽  
Secretory Granules ◽  
Secretory Activity ◽  
Α Subunit ◽  
Capacitance Measurements ◽  
Regulated Secretion ◽  
Kinetic Component ◽  
Membrane Bound

Besides having a role in signal transduction some trimeric G-proteins may be involved in a late stage of exocytosis. Using immunocytochemistry and confocal microscopy we found that Gi(3)-protein resides mainly in the plasma membrane, whereas Gi(1/2-)protein is preferentially associated with secretory granules. To study the function of trimeric Gi(3)- and Gi(1/2)-proteins, secretory responses in single rat melanotrophs were monitored by patch-clamp membrane capacitance measurements. We report here that mastoparan, an activator of trimeric G-proteins, enhances calcium-induced secretory activity in rat melanotrophs. The introduction of synthetic peptides corresponding to the C-terminal domain of the (α)-subunit of Gi(3)- and Gi(1/2)-proteins indicated that Gi(3)peptide specifically blocked the mastoparan-stimulated secretory activity, which indicates an involvement of a trimeric Gi(3)-protein in mastoparan-stimulated secretory activity. Flash photolysis of caged Ca(2+)-elicited biphasic capacitance increases consisting of a fast and a slower component. Injection of anti-Gi(3) antibodies selectively inhibited the slow but not the fast component of secretory activity in rat melanotrophs. We propose that the plasma membrane-bound Gi(3)-protein may be involved in regulated secretion by specifically controlling the slower kinetic component of exocytosis.

FC20 ribose modified adenosine analogues as potential partial agonists for the adenosine receptor

1994 ◽  
Vol 2 (1-2) ◽  
pp. 105 ◽  
Author(s):  
E.M. van der Wenden ◽  
J.K. Künzel ◽  
R.A.A. Mathôt ◽  
A.P. Ijzeman ◽  
M. Danhof ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Adenosine Analogues ◽  
Partial Agonists

scholarly journals A2B Adenosine Receptor and Cancer

2019 ◽  
Vol 20 (20) ◽  
pp. 5139 ◽  
Author(s):  
Zhan-Guo Gao ◽  
Kenneth A. Jacobson
Keyword(s):  
G Proteins ◽  
Anticancer Agents ◽  
Immune Suppression ◽  
Adenosine Receptors ◽  
Immune Surveillance ◽  
G Protein Coupled Receptors ◽  
Normal Tissues ◽  
Cancer Tissues ◽  
G Protein Coupled

There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A2BAR, coupled to both Gαs and Gαi G proteins, is one of the several GPCRs that are expressed in a significantly higher level in certain cancer tissues, in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various cancers, and the rationale of using A2BAR antagonists in cancer therapy.

Effect of adenosine receptor blockade: preventing protective preconditioning depends on time of initiation

1993 ◽  
Vol 265 (2) ◽  
pp. H504-H508 ◽  
Author(s):  
J. D. Thornton ◽  
C. S. Thornton ◽  
J. M. Downey
Keyword(s):  
Protective Effect ◽  
Ischemic Preconditioning ◽  
Adenosine Receptor ◽  
Adenosine Receptors ◽  
Receptor Blockade ◽  
Risk Zone ◽  
Time Points ◽  
Adenosine Receptor Antagonist ◽  
Rabbit Myocardium ◽  
Ischemic Period

Ischemic preconditioning protects the rabbit myocardium from infarction from a subsequent ischemia, and adenosine receptors appear to be involved in this protection. The present study attempts to determine when adenosine receptors must be occupied to achieve protection by infusing the adenosine receptor antagonist PD-115,199 at various time points during the study. Open-chest rabbits were subjected to 30 min of regional ischemia followed by 3 h of reperfusion and had 38 +/- 4% infarction of the risk zone. When hearts were preconditioned by 5 min of ischemia and 10 min reperfusion before the 30-min period of ischemia, only 9 +/- 2% infarction occurred. PD-115,199 given 5 min before the ischemic preconditioning episode blocked the protective effect of preconditioning (39 +/- 5% infarction). PD-115,199 also blocked the protection when given between the ischemic preconditioning episode and the 30-min period of ischemia (30 +/- 4% infarction). PD-115,199 given at the end of 30 min of ischemia did not block protection in preconditioned (PC) hearts (17 +/- 5% infarction) and had no effect on non-PC hearts (44 +/- 6% infarction). In prior studies we found that exogenous adenosine could substitute for ischemia to precondition the heart, indicating that adenosine is an initiator of preconditioning. These results, however, indicate that adenosine receptors must also be occupied during the long ischemic period for preconditioning to be protective and suggest that adenosine is a mediator of preconditioning as well.

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