International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

Special Issue: G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond

by Francisco Ciruela

Int. J. Mol. Sci. 2020, 21(6), 1997; https://doi.org/10.3390/ijms21061997 - 15 Mar 2020

Cited by 1 | Viewed by 1955

Abstract

Adenosine is a purine nucleoside present in all human cells where it plays many different physiological roles: From being a building block for nucleic acids to a key constituent of the biological energy currency ATP [...] Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

Research

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14 pages, 1539 KiB

Open AccessCommunication

Development of a Radiofluorinated Adenosine A_2B Receptor Antagonist as Potential Ligand for PET Imaging

by Marcel Lindemann, Rareş-Petru Moldovan, Sonja Hinz, Winnie Deuther-Conrad, Daniel Gündel, Sladjana Dukic-Stefanovic, Magali Toussaint, Rodrigo Teodoro, Cathleen Juhl, Jörg Steinbach, Peter Brust, Christa E. Müller and Barbara Wenzel

Int. J. Mol. Sci. 2020, 21(9), 3197; https://doi.org/10.3390/ijms21093197 - 30 Apr 2020

Cited by 4 | Viewed by 3008

Abstract

The adenosine A_2B receptor has been proposed as a novel therapeutic target in cancer, as its expression is drastically elevated in several tumors and cancer cells. Noninvasive molecular imaging via positron emission tomography (PET) would allow the in vivo quantification of this [...] Read more.

The adenosine A_2B receptor has been proposed as a novel therapeutic target in cancer, as its expression is drastically elevated in several tumors and cancer cells. Noninvasive molecular imaging via positron emission tomography (PET) would allow the in vivo quantification of this receptor in pathological processes and most likely enable the identification and clinical monitoring of respective cancer therapies. On the basis of a bicyclic pyridopyrimidine-2,4-dione core structure, the new adenosine A_2B receptor ligand 9 was synthesized, containing a 2-fluoropyridine moiety suitable for labeling with the short-lived PET radionuclide fluorine-18. Compound 9 showed a high binding affinity for the human A_2B receptor (K_i(A_2B) = 2.51 nM), along with high selectivities versus the A₁, A_2A, and A₃ receptor subtypes. Therefore, it was radiofluorinated via nucleophilic aromatic substitution of the corresponding nitro precursor using [¹⁸F]F^-/K_2.2.2./K₂CO₃ in DMSO at 120 °C. Metabolic studies of [¹⁸F]9 in mice revealed about 60% of radiotracer intact in plasma at 30 minutes p.i. A preliminary PET study in healthy mice showed an overall biodistribution of [¹⁸F]9, corresponding to the known ubiquitous but low expression of the A_2B receptor. Consequently, [¹⁸F]9 represents a novel PET radiotracer with high affinity and selectivity toward the adenosine A_2B receptor and a suitable in vivo profile. Subsequent studies are envisaged to investigate the applicability of [¹⁸F]9 to detect alterations in the receptor density in certain cancer-related disease models. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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14 pages, 2671 KiB

Open AccessArticle

PDRN, a Bioactive Natural Compound, Ameliorates Imiquimod-Induced Psoriasis through NF-κB Pathway Inhibition and Wnt/β-Catenin Signaling Modulation

by Natasha Irrera, Alessandra Bitto, Mario Vaccaro, Federica Mannino, Violetta Squadrito, Giovanni Pallio, Vincenzo Arcoraci, Letteria Minutoli, Antonio Ieni, Maria Lentini, Domenica Altavilla and Francesco Squadrito

Int. J. Mol. Sci. 2020, 21(4), 1215; https://doi.org/10.3390/ijms21041215 - 12 Feb 2020

Cited by 22 | Viewed by 5668

Abstract

Nuclear factor-κB (NF-κB) plays a central role in psoriasis and canonical Wnt/β-catenin pathway blunts the immune-mediated inflammatory cascade in psoriasis. Adenosine A2A receptor activation blocks NF-κB and boosts the Wnt/β-catenin signaling. PDRN (Polydeoxyribonucleotide) is a biologic agonist of the A2A receptor and its [...] Read more.

Nuclear factor-κB (NF-κB) plays a central role in psoriasis and canonical Wnt/β-catenin pathway blunts the immune-mediated inflammatory cascade in psoriasis. Adenosine A2A receptor activation blocks NF-κB and boosts the Wnt/β-catenin signaling. PDRN (Polydeoxyribonucleotide) is a biologic agonist of the A2A receptor and its effects were studied in an experimental model of psoriasis. Psoriasis-like lesions were induced by a daily application of imiquimod (IMQ) on the shaved back skin of mice for 7 days. Animals were randomly assigned to the following groups: Sham psoriasis challenged with Vaseline; IMQ animals challenged with imiquimod; and IMQ animals treated with PDRN (8 mg/kg/ip). An additional arm of IMQ animals was treated with PDRN plus istradefylline (KW6002; 25 mg/kg/ip) as an A2A antagonist. PDRN restored a normal skin architecture, whereas istradefylline abrogated PDRN positive effects, thus pointing out the mechanistic role of the A2A receptor. PDRN decreased pro-inflammatory cytokines, prompted Wnt signaling, reduced IL-2 and increased IL-10. PDRN also reverted the LPS repressed Wnt-1/β-catenin in human keratinocytes and these effects were abolished by ZM241385, an A2A receptor antagonist. Finally, PDRN reduced CD3+ cells in superficial psoriatic dermis. PDRN anti-psoriasis potential may be linked to a “dual mode” of action: NF-κB inhibition and Wnt/β-catenin stimulation. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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16 pages, 1734 KiB

Open AccessArticle

Adenosine Suppresses Cholangiocarcinoma Cell Growth and Invasion in Equilibrative Nucleoside Transporters-Dependent Pathway

by Kornkamon Lertsuwan, Supathra Phoaubon, Nathapol Tasnawijitwong and Jomnarong Lertsuwan

Int. J. Mol. Sci. 2020, 21(3), 814; https://doi.org/10.3390/ijms21030814 - 27 Jan 2020

Cited by 6 | Viewed by 4100

Abstract

Cholangiocarcinoma (CCA) is a lethal disease with increasing incidence worldwide. Previous study showed that CCA was sensitive to adenosine. Thereby, molecular mechanisms of CCA inhibition by adenosine were examined in this study. Our results showed that adenosine inhibited CCA cells via an uptake [...] Read more.

Cholangiocarcinoma (CCA) is a lethal disease with increasing incidence worldwide. Previous study showed that CCA was sensitive to adenosine. Thereby, molecular mechanisms of CCA inhibition by adenosine were examined in this study. Our results showed that adenosine inhibited CCA cells via an uptake of adenosine through equilibrative nucleoside transporters (ENTs), instead of activation of adenosine receptors. The inhibition of ENTs by NBTI caused the inhibitory effect of adenosine to subside, while adenosine receptor antagonists, caffeine and CGS-15943, failed to do so. Intracellular adenosine level was increased after adenosine treatment. Also, a conversion of adenosine to AMP by adenosine kinase is required in this inhibition. On the other hand, inosine, which is a metabolic product of adenosine has very little inhibitory effect on CCA cells. This indicates that a conversion of adenosine to inosine may reduce adenosine inhibitory effect. Furthermore, there was no specific correlation between level of proinflammatory proteins and CCA responses to adenosine. A metabolic stable analog of adenosine, 2Cl-adenosine, exerted higher inhibition on CCA cell growth. The disturbance in intracellular AMP level also led to an activation of 5′ AMP-activated protein kinase (AMPK). Accordingly, we proposed a novel adenosine-mediated cancer cell growth and invasion suppression via a receptor-independent mechanism in CCA. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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14 pages, 719 KiB

Open AccessArticle

Accuracy and Precision of the Receptorial Responsiveness Method (RRM) in the Quantification of A₁ Adenosine Receptor Agonists

by Adrienn Monika Szabo, Gabor Viczjan, Tamas Erdei, Ildiko Simon, Rita Kiss, Andras Jozsef Szentmiklosi, Bela Juhasz, Csaba Papp, Judit Zsuga, Akos Pinter, Zoltan Szilvassy and Rudolf Gesztelyi

Int. J. Mol. Sci. 2019, 20(24), 6264; https://doi.org/10.3390/ijms20246264 - 12 Dec 2019

Cited by 3 | Viewed by 2588

Abstract

The receptorial responsiveness method (RRM) is a procedure that is based on a simple nonlinear regression while using a model with two variables (X, Y) and (at least) one parameter to be determined (c_x). The model of RRM describes the co-action [...] Read more.

The receptorial responsiveness method (RRM) is a procedure that is based on a simple nonlinear regression while using a model with two variables (X, Y) and (at least) one parameter to be determined (c_x). The model of RRM describes the co-action of two agonists that consume the same response capacity (due to the use of the same postreceptorial signaling in a biological system). While using RRM, uniquely, an acute increase in the concentration of an agonist (near the receptors) can be quantified (as c_x), via evaluating E/c curves that were constructed with the same or another agonist in the same system. As this measurement is sensitive to the implementation of the curve fitting, the goal of the present study was to test RRM by combining different ways and setting options, namely: individual vs. global fitting, ordinary vs. robust fitting, and three weighting options (no weighting vs. weighting by 1/Y² vs. weighting by 1/SD²). During the testing, RRM was used to estimate the known concentrations of stable synthetic A₁ adenosine receptor agonists in isolated, paced guinea pig left atria. The estimates were then compared to the known agonist concentrations (to assess the accuracy of RRM); furthermore, the 95% confidence limits of the best-fit values were also considered (to evaluate the precision of RRM). It was found that, although the global fitting offered the most convenient way to perform RRM, the best estimates were provided by the individual fitting without any weighting, almost irrespective of the fact whether ordinary or robust fitting was chosen. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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14 pages, 1695 KiB

Open AccessArticle

A2AR Transmembrane 2 Peptide Administration Disrupts the A2AR-A2AR Homoreceptor but Not the A2AR-D2R Heteroreceptor Complex: Lack of Actions on Rodent Cocaine Self-Administration

by Dasiel O. Borroto-Escuela, Karolina Wydra, Wilber Romero-Fernandez, Zilong Zhou, Malgorzata Frankowska, Malgorzata Filip and Kjell Fuxe

Int. J. Mol. Sci. 2019, 20(23), 6100; https://doi.org/10.3390/ijms20236100 - 3 Dec 2019

Cited by 8 | Viewed by 3231

Abstract

It was previously demonstrated that rat adenosine A2AR transmembrane V peptide administration into the nucleus accumbens enhances cocaine self-administration through disruption of the A2AR-dopamine (D2R) heteroreceptor complex of this region. Unlike human A2AR transmembrane 4 (TM4) and 5 (TM5), A2AR TM2 did not [...] Read more.

It was previously demonstrated that rat adenosine A2AR transmembrane V peptide administration into the nucleus accumbens enhances cocaine self-administration through disruption of the A2AR-dopamine (D2R) heteroreceptor complex of this region. Unlike human A2AR transmembrane 4 (TM4) and 5 (TM5), A2AR TM2 did not interfere with the formation of the A2AR-D2R heteroreceptor complex in cellular models using BRET¹ assay. A2AR TM2 was proposed to be part of the of the receptor interface of the A2AR homomer instead and was therefore tested in the current article for effects on rat cocaine self-administration using rat A2AR synthetic TM2 peptide bilaterally injected into the nucleus accumbens. The injected A2AR TM2 peptide failed to significantly counteract the inhibitory action of the A2AR agonist CGS 21680 (0.1 mg/Kg) on cocaine self-administration. In line with these results, the microinjected A2AR TM2 peptide did not reduce the number of proximity ligation assay blobs identifying A2AR-D2R heteroreceptor complexes in the nucleus accumbens. In contrast, the A2AR TM2 peptide significantly reduced the number of A2AR-A2AR homoreceptor complexes in the nucleus accumbens. As to effects on the receptor–receptor interactions in the A2AR-D2R heteroreceptor complexes, the A2AR TM2 peptide did not alter the significant increase in the D2R Ki, high values produced by the A2AR agonist CGS 21680 ex vivo in the ventral striatum. The results indicate that the accumbal A2AR-A2AR homomeric complexes are not involved in mediating the A2AR agonist-induced inhibition of cocaine self-administration. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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16 pages, 5591 KiB

Open AccessArticle

Expression of Adenosine Receptors in Rodent Pancreas

by Mikio Hayashi

Int. J. Mol. Sci. 2019, 20(21), 5329; https://doi.org/10.3390/ijms20215329 - 25 Oct 2019

Cited by 11 | Viewed by 3475

Abstract

Adenosine regulates exocrine and endocrine secretions in the pancreas. Adenosine is considered to play a role in acini-to-duct signaling in the exocrine pancreas. To identify the molecular basis of functional adenosine receptors in the exocrine pancreas, immunohistochemical analysis was performed in the rat, [...] Read more.

Adenosine regulates exocrine and endocrine secretions in the pancreas. Adenosine is considered to play a role in acini-to-duct signaling in the exocrine pancreas. To identify the molecular basis of functional adenosine receptors in the exocrine pancreas, immunohistochemical analysis was performed in the rat, mouse, and guinea pig pancreas, and the secretory rate and concentration of HCO₃⁻ in pancreatic juice from the rat pancreas were measured. The A_2A adenosine receptor colocalized with ezrin, an A-kinase anchoring protein, in the luminal membrane of duct cells in the mouse and guinea pig pancreas. However, a strong signal ascribed to A_2B adenosine receptors was detected in insulin-positive β cells in islets of Langerhans. The A_2A adenosine receptor agonist 4-[2-[[6-Amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid (CGS 21680) stimulated HCO₃⁻-rich fluid secretion from the rat pancreas. These results indicate that A_2A adenosine receptors may be, at least in part, involved in the exocrine secretion of pancreatic duct cells via acini-to-duct signaling. The adenosine receptors may be a potential therapeutic target for cancer as well as exocrine dysfunctions of the pancreas. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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22 pages, 2850 KiB

Open AccessArticle

Carbamazepine Attenuates Astroglial L-Glutamate Release Induced by Pro-Inflammatory Cytokines via Chronically Activation of Adenosine A_2A Receptor

by Motohiro Okada, Kouji Fukuyama, Takashi Shiroyama and Yuto Ueda

Int. J. Mol. Sci. 2019, 20(15), 3727; https://doi.org/10.3390/ijms20153727 - 30 Jul 2019

Cited by 21 | Viewed by 4261

Abstract

Carbamazepine (CBZ) binds adenosine receptors, but detailed effects of CBZ on astroglial transmission associated with adenosine receptor still need to be clarified. To clarify adenosinergic action of CBZ on astroglial transmission, primary cultured astrocytes were acutely or chronically treated with CBZ, proinflammatory cytokines [...] Read more.

Carbamazepine (CBZ) binds adenosine receptors, but detailed effects of CBZ on astroglial transmission associated with adenosine receptor still need to be clarified. To clarify adenosinergic action of CBZ on astroglial transmission, primary cultured astrocytes were acutely or chronically treated with CBZ, proinflammatory cytokines (interferon γ (IFNγ) and tumor necrosis factor α (TNFα)), and adenosine A2A receptor (A2AR) agonist (CGS21680). IFNγ and TNFα increased basal, adenophostin-A (AdA)-evoked, and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)-evoked astroglial L-glutamate releases. In physiological condition, CGS21680 increased basal astroglial L-glutamate release but glutamate transporter inhibition prevented this CGS21680 action. CBZ did not affect basal release, whereas glutamate transporter inhibition generated CBZ-induced glutamate release. Furthermore, AdA-evoked and AMPA-evoked releases were inhibited by CBZ but were unaffected by CGS21680. Contrary to physiological condition, chronic administrations of IFNγ and TNFα enhanced basal, AdA-, and AMPA-evoked releases, whereas IFNγ and TNFα decreased and increased CGS21680-evoked releases via modulation A2AR expression. Both chronic administration of CGS21680 and CBZ suppressed astroglial L-glutamate release responses induced by chronic cytokine exposer. Especifically, chronic administration of CBZ and CGS21680 prevented the reduction and elevation of A2AR expression by respective IFNγ and TNFα. These findings suggest that A2AR agonistic effects of CBZ contribute to chronic prevention of pathomechanisms developments of several neuropsychiatric disorders associated with proinflammatory cytokines. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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12 pages, 1480 KiB

Open AccessArticle

Bioluminescence Resonance Energy Transfer Based G Protein-Activation Assay to Probe Duration of Antagonism at the Histamine H₃ Receptor

by Tamara A. M. Mocking, Maurice C. M. L. Buzink, Rob Leurs and Henry F. Vischer

Int. J. Mol. Sci. 2019, 20(15), 3724; https://doi.org/10.3390/ijms20153724 - 30 Jul 2019

Cited by 7 | Viewed by 4466

Abstract

Duration of receptor antagonism, measured as the recovery of agonist responsiveness, is gaining attention as a method to evaluate the ‘effective’ target-residence for antagonists. These functional assays might be a good alternative for kinetic binding assays in competition with radiolabeled or fluorescent ligands, [...] Read more.

Duration of receptor antagonism, measured as the recovery of agonist responsiveness, is gaining attention as a method to evaluate the ‘effective’ target-residence for antagonists. These functional assays might be a good alternative for kinetic binding assays in competition with radiolabeled or fluorescent ligands, as they are performed on intact cells and better reflect consequences of dynamic cellular processes on duration of receptor antagonism. Here, we used a bioluminescence resonance energy transfer (BRET)-based assay that monitors heterotrimeric G protein activation via scavenging of released Venus-Gβ₁γ₂ by NanoLuc (Nluc)-tagged membrane-associated-C-terminal fragment of G protein-coupled receptor kinase 3 (masGRK3ct-Nluc) as a tool to probe duration of G protein-coupled receptor (GPCR) antagonism. The Gα_i-coupled histamine H₃ receptor (H₃R) was used in this study as prolonged antagonism is associated with adverse events (e.g., insomnia) and consequently, short-residence time ligands might be preferred. Due to its fast and prolonged response, this assay can be used to determine the duration of functional antagonism by measuring the recovery of agonist responsiveness upon washout of pre-bound antagonist, and to assess antagonist re-equilibration time via Schild-plot analysis. Re-equilibration of pre-incubated antagonist with agonist and receptor could be followed in time to monitor the transition from insurmountable to surmountable antagonism. The BRET-based G protein activation assay can detect differences in the recovery of H₃R responsiveness and re-equilibration of pre-bound antagonists between the tested H₃R antagonists. Fast dissociation kinetics were observed for marketed drug pitolisant (Wakix^®) in this assay, which suggests that short residence time might be beneficial for therapeutic targeting of the H₃R. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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11 pages, 1903 KiB

Open AccessArticle

Revealing Adenosine A_2A-Dopamine D₂ Receptor Heteromers in Parkinson’s Disease Post-Mortem Brain through a New AlphaScreen-Based Assay

by Víctor Fernández-Dueñas, Maricel Gómez-Soler, Marta Valle-León, Masahiko Watanabe, Isidre Ferrer and Francisco Ciruela

Int. J. Mol. Sci. 2019, 20(14), 3600; https://doi.org/10.3390/ijms20143600 - 23 Jul 2019

Cited by 34 | Viewed by 6042

Abstract

Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human [...] Read more.

Background: Several biophysical techniques have been successfully implemented to detect G protein-coupled receptors (GPCRs) heteromerization. Although these approaches have made it possible to ascertain the presence of GPCR heteromers in animal models of disease, no success has been accomplished in pathological human post-mortem brains. The AlphaScreen technology has been consistently used to quantify small analyte accumulation or depletion, bimolecular interactions, and post-translational modifications. The high signal-to-background, dynamic range and sensitivity exhibited by this technology support that it may be suitable to detect GPCR heteromers even under non-optimal conditions. Methods: Here, we describe the development of a new AlphaScreen assay to detect GPCR oligomers in human post-mortem brain. Results: Adenosine A2A-dopamine D2 receptor (A2AR/D2R) heteromer formation was monitored in caudate from healthy and Parkinson’s disease (PD) subjects. The approach was first validated using striatal membranes from wild type and A2AR deficient mice. Secondly, we took advantage of the 6-hydroxydopamine hemiparkinsonian rat model to validate previous results. In addition, finally, A2AR/D2R heteromer formation was assessed in caudate membranes from human post-mortem brains. Importantly, our preliminary results revealed an increase in A2AR/D2R heteromer formation in PD brains. Conclusions: The new AlphaScreen assay allowed assessing GPCR heteromers in human post-mortem brains with high sensitivity. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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12 pages, 1318 KiB

Open AccessCommunication

A2A-D2 Heteromers on Striatal Astrocytes: Biochemical and Biophysical Evidence

by Simone Pelassa, Diego Guidolin, Arianna Venturini, Monica Averna, Giulia Frumento, Letizia Campanini, Rosa Bernardi, Pietro Cortelli, Giovanna Calandra Buonaura, Guido Maura, Luigi F. Agnati, Chiara Cervetto and Manuela Marcoli

Int. J. Mol. Sci. 2019, 20(10), 2457; https://doi.org/10.3390/ijms20102457 - 17 May 2019

Cited by 28 | Viewed by 3570

Abstract

Our previous findings indicate that A2A and D2 receptors are co-expressed on adult rat striatal astrocytes and on the astrocyte processes, and that A2A-D2 receptor–receptor interaction can control the release of glutamate from the processes. Functional evidence suggests that the receptor–receptor interaction was [...] Read more.

Our previous findings indicate that A2A and D2 receptors are co-expressed on adult rat striatal astrocytes and on the astrocyte processes, and that A2A-D2 receptor–receptor interaction can control the release of glutamate from the processes. Functional evidence suggests that the receptor–receptor interaction was based on heteromerization of native A2A and D2 receptors at the plasma membrane of striatal astrocyte processes. We here provide biochemical and biophysical evidence confirming that receptor–receptor interaction between A2A and D2 receptors at the astrocyte plasma membrane is based on A2A-D2 heteromerization. To our knowledge, this is the first direct demonstration of the ability of native A2A and D2 receptors to heteromerize on glial cells. As striatal astrocytes are recognized to be involved in Parkinson’s pathophysiology, the findings that adenosine A2A and dopamine D2 receptors can form A2A-D2 heteromers on the astrocytes in the striatum (and that these heteromers can play roles in the control of the striatal glutamatergic transmission) may shed light on the molecular mechanisms involved in the pathogenesis of the disease. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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Review

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13 pages, 2026 KiB

Open AccessReview

Adenosine Receptor Profiling Reveals an Association between the Presence of Spare Receptors and Cardiovascular Disorders

by Emmanuel Fenouillet, Giovanna Mottola, Nathalie Kipson, Franck Paganelli, Régis Guieu and Jean Ruf

Int. J. Mol. Sci. 2019, 20(23), 5964; https://doi.org/10.3390/ijms20235964 - 27 Nov 2019

Cited by 22 | Viewed by 6625

Abstract

Adenosine and its receptors exert a potent control on the cardiovascular system. This review aims to present emerging experimental evidence supporting the existence and implication in cardiovascular disorders of specific adenosinergic pharmacological profiles, conforming to the concept of “receptor reserve”, also known as [...] Read more.

Adenosine and its receptors exert a potent control on the cardiovascular system. This review aims to present emerging experimental evidence supporting the existence and implication in cardiovascular disorders of specific adenosinergic pharmacological profiles, conforming to the concept of “receptor reserve”, also known as “spare receptors”. This kind of receptors allow agonists to achieve their maximal effect without occupying all of the relevant cell receptors. In the cardiovascular system, spare adenosine receptors appear to compensate for a low extracellular adenosine level and/or a low adenosine receptor number, such as in coronary artery disease or some kinds of neurocardiogenic syncopes. In both cases, the presence of spare receptors appears to be an attempt to overcome a weak interaction between adenosine and its receptors. The identification of adenosine spare receptors in cardiovascular disorders may be helpful for diagnostic purposes. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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18 pages, 4135 KiB

Open AccessReview

Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy

by Nina Wolska and Marcin Rozalski

Int. J. Mol. Sci. 2019, 20(21), 5475; https://doi.org/10.3390/ijms20215475 - 3 Nov 2019

Cited by 31 | Viewed by 6415

Abstract

Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A_2A and A_2B) of the four known adenosine receptor subtypes (A [...] Read more.

Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A_2A and A_2B) of the four known adenosine receptor subtypes (A₁, A_2A, A_2B, and A₃). Agonization of these receptors results in an enhanced intracellular cAMP and the inhibition of platelet activation and aggregation. Therefore, adenosine receptors A_2A and A_2B could be targets for anti-platelet therapy, especially under circumstances when classic therapy based on antagonizing the purinergic receptor P2Y₁₂ is insufficient or problematic. Apart from adenosine, there is a group of synthetic, selective, longer-lasting agonists of A_2A and A_2B receptors reported in the literature. This group includes agonists with good selectivity for A_2A or A_2B receptors, as well as non-selective compounds that activate more than one type of adenosine receptor. Chemically, most A_2A and A_2B adenosine receptor agonists are adenosine analogues, with either adenine or ribose substituted by single or multiple foreign substituents. However, a group of non-adenosine derivative agonists has also been described. This review aims to systematically describe known agonists of A_2A and A_2B receptors and review the available literature data on their effects on platelet function. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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18 pages, 694 KiB

Open AccessReview

A_2B Adenosine Receptor and Cancer

by Zhan-Guo Gao and Kenneth A. Jacobson

Int. J. Mol. Sci. 2019, 20(20), 5139; https://doi.org/10.3390/ijms20205139 - 17 Oct 2019

Cited by 64 | Viewed by 7369

Abstract

There are four subtypes of adenosine receptors (ARs), named A₁, A_2A, A_2B and A₃, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A_2BAR, [...] Read more.

There are four subtypes of adenosine receptors (ARs), named A₁, A_2A, A_2B and A₃, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A_2BAR, 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 A_2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A_2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A_2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A_2BAR. We further discuss the role of the A_2BAR in the progression of various cancers, and the rationale of using A_2BAR antagonists in cancer therapy. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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35 pages, 758 KiB

Open AccessReview

The Biological and Clinical Relevance of G Protein-Coupled Receptors to the Outcomes of Hematopoietic Stem Cell Transplantation: A Systematized Review

by Hadrien Golay, Simona Jurkovic Mlakar, Vid Mlakar, Tiago Nava and Marc Ansari

Int. J. Mol. Sci. 2019, 20(16), 3889; https://doi.org/10.3390/ijms20163889 - 9 Aug 2019

Cited by 3 | Viewed by 4553

Abstract

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for several malignant and non-malignant diseases at the cost of serious treatment-related toxicities (TRTs). Recent research on extending the benefits of HSCT to more patients and indications has focused on limiting TRTs and [...] Read more.

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for several malignant and non-malignant diseases at the cost of serious treatment-related toxicities (TRTs). Recent research on extending the benefits of HSCT to more patients and indications has focused on limiting TRTs and improving immunological effects following proper mobilization and engraftment. Increasing numbers of studies report associations between HSCT outcomes and the expression or the manipulation of G protein-coupled receptors (GPCRs). This large family of cell surface receptors is involved in various human diseases. With ever-better knowledge of their crystal structures and signaling dynamics, GPCRs are already the targets for one third of the current therapeutic arsenal. The present paper assesses the current status of animal and human research on GPCRs in the context of selected HSCT outcomes via a systematized survey and analysis of the literature. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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