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BBA - Biomembranes (v.1808, #5)
Structural features of adenosine receptors: From crystal to function by Henni Piirainen; Yashwanth Ashok; Rahul T. Nanekar; Veli-Pekka Jaakola (pp. 1233-1244).
The important role that extracellular adenosine plays in many physiological processes is mediated by the adenosine class of G protein-coupled receptors, a class of receptors that also responds to the antagonist caffeine, the most widely used pharmacological agent in the world. The crystallographic model of the human adenosine A2A receptor was recently solved to 2.6Å in complex with the antagonist ZM241385, which is also referred to as “ super-caffeine” because of its strong antagonistic effect on adenosine receptors. The crystallographic model revealed some unexpected and unusual features of the adenosine A2A receptor structure that have led to new studies on the receptor and the re-examination of pre-existing data. Compared to other known GPCR structures, the adenosine A2A receptor has a unique ligand binding pocket that is nearly perpendicular to the membrane plane. The ligand binding site highlights the integral role of the helical core together with the extracellular loops and the four disulfide bridges in the extracellular domain, in ligand recognition by the adenosine class of GPCRs. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: G protein-coupled receptor; Heptahelical transmembrane protein; 7-TM; Adenosine receptor; Signal transduction; Structure; Site-directed mutagenesis
Adenosine receptor containing oligomers: Their role in the control of dopamine and glutamate neurotransmission in the brain by Francisco Ciruela; Gomez-Soler Maricel Gómez-Soler; Diego Guidolin; Dasiel O. Borroto-Escuela; Luigi F. Agnati; Kjell Fuxe; Fernandez-Duenas Víctor Fernández-Dueñas (pp. 1245-1255).
While the G protein-coupled receptor (GPCR) oligomerization has been questioned during the last fifteen years, the existence of a multi-receptor complex involving direct receptor–receptor interactions, called receptor oligomers, begins to be widely accepted. Eventually, it has been postulated that oligomers constitute a distinct functional form of the GPCRs with essential receptorial features. Also, it has been proven, under certain circumstances, that the GPCR oligomerization phenomenon is crucial for the receptor biosynthesis, maturation, trafficking, plasma membrane diffusion, and pharmacology and signalling. Adenosine receptors are GPCRs that mediate the physiological functions of adenosine and indeed these receptors do also oligomerize. Accordingly, adenosine receptor oligomers may improve the molecular mechanism by which extracellular adenosine signals are transferred to the G proteins in the process of receptor transduction. Importantly, these adenosine receptor-containing oligomers may allow not only the control of the adenosinergic function but also the fine-tuning modulation of other neurotransmitter systems (i.e. dopaminergic and glutamatergic transmission). Overall, we underscore here recent significant developments based on adenosine receptor oligomerization that are essential for acquiring a better understanding of neurotransmission in the central nervous system under normal and pathological conditions. This article is part of a Special Issue entitled: “Adenosine Receptors”.► Adenosine receptors (AR) form oligomers. ► AR oligomers improve the molecular mechanism by which adenosine activates G proteins. ► AR oligomers synchronize wiring transmission vs volume transmission. ► AR oligomers control the dopamine and glutamate neurotransmission.
Keywords: G protein-coupled receptors; Adenosine receptors; Protein–protein interaction; GPCR oligomerization
Dimerization and ligand binding affect the structure network of A2A adenosine receptor by Francesca Fanelli; Angelo Felline (pp. 1256-1266).
G protein Coupled Receptors (GPCRs) are allosteric proteins whose functioning fundamentals are the communication between the two poles of the helix bundle. The representation of GPCR structures as networks of interacting amino acids can be a meaningful way to decipher the impact of ligand and of dimerization/oligomerization on the molecular communication intrinsic to the protein fold. In this study, we predicted likely homodimer architectures of the A2AR and investigated the effects of dimerization on the structure network and the communication paths of the monomeric form. The results of this study emphasize the roles of helix 1 in A2AR dimerization and of highly conserved amino acids in helices 1, 2, 6 and 7 in maintaining the structure network of the A2AR through a persistent hub behavior as well as in the information flow between the extracellular and intracellular poles of the helix bundle. The arginine of the conserved E/DRY motif, R3.50, is not involved in the communication paths but participates in the structure network as a stable hub, being linked to both D3.49 and E6.30 like in the inactive states of rhodopsin. A2AR dimerization affects the communication networks intrinsic to the receptor fold in a way dependent on the dimer architecture. Certain architectures retain the most recurrent communication paths with respect to the monomeric antagonist-bound form but enhancing path numbers and frequencies, whereas some others impair ligand-mediated communication networks. Ligand binding affects the network as well. Overall, the communication network that pertains to the functional dynamics of a GPCR is expected to be influenced by ligand functionality, oligomeric order and architecture of the supramolecular assembly. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: Intramolecular and intermolecular communication; Protein Structure Network; GPCR dimerization; Molecular Dynamics simulations
Bioinformatics and mathematical modelling in the study of receptor–receptor interactions and receptor oligomerization by Diego Guidolin; Francisco Ciruela; Susanna Genedani; Michele Guescini; Cinzia Tortorella; Giovanna Albertin; Kjell Fuxe; Luigi Francesco Agnati (pp. 1267-1283).
The concept of intra-membrane receptor–receptor interactions (RRIs) between different types of G protein-coupled receptors (GPCRs) and evidence for their existence was introduced by Agnati and Fuxe in 1980/81 through the biochemical analysis of the effects of neuropeptides on the binding characteristics of monoamine receptors in membrane preparations from discrete brain regions and functional studies of the interactions between neuropeptides and monoamines in the control of specific functions such as motor control and arterial blood pressure control in animal models.Whether GPCRs can form high-order structures is still a topic of an intense debate. Increasing evidence, however, suggests that the hypothesis of the existence of high-order receptor oligomers is correct. A fundamental consequence of the view describing GPCRs as interacting structures, with the likely formation at the plasma membrane of receptor aggregates of multiple receptors (Receptor Mosaics) is that it is no longer possible to describe signal transduction simply as the result of the binding of the chemical signal to its receptor, but rather as the result of a filtering/integration of chemical signals by the Receptor Mosaics (RMs) and membrane-associated proteins. Thus, in parallel with experimental research, significant efforts were spent in bioinformatics and mathematical modelling. We review here the main approaches that have been used to assess the interaction interfaces allowing the assembly of GPCRs and to shed some light on the integrative functions emerging from the complex behaviour of these RMs. Particular attention was paid to the RMs generated by adenosine A2A, dopamine D2, cannabinoid CB1, and metabotropic glutamate mGlu5 receptors (A2A, D2, CB1 and mGlu5, respectively), and a possible approach to model the interplay between the D2–A2A–CB1 and D2–A2A–mGlu5 trimers is proposed. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: Bioinformatic; G protein-coupled receptor; Oligomerization; Receptor–receptor interaction; Receptor Mosaic; Allosterism; Adenosine receptor
Adenosine receptors and membrane microdomains by Robert D. Lasley (pp. 1284-1289).
Adenosine receptors are a member of the large family of seven transmembrane spanning G protein coupled receptors. The four adenosine receptor subtypes—A1, A2a, A2b, A3—exert their effects via the activation of one or more heterotrimeric G proteins resulting in the modulation of intracellular signaling. Numerous studies over the past decade have documented the complexity of G protein coupled receptor signaling at the level of protein–protein interactions as well as through signaling cross talk. With respect to adenosine receptors, the activation of one receptor subtype can have profound direct effects in one cell type but little or no effect in other cells. There is significant evidence that the compartmentation of subcellular signaling plays a physiological role in the fidelity of G protein coupled receptor signaling. This compartmentation is evident at the level of the plasma membrane in the form of membrane microdomains such as caveolae and lipid rafts. This review will summarize and critically assess our current understanding of the role of membrane microdomains in regulating adenosine receptor signaling. This article is part of a Special Issue entitled: “Adenosine Receptors”.►A1 adenosine receptors in cardiomyocytes are localized in caveolae. ►A1 adenosine receptors in other cell types appear to internalize via caveolae. ►A2a adenosine receptors may be concentrated in cholesterol enriched membrane domains. ►There is no evidence to date for localization of A2b or A3 receptors in membrane microdomains.
Keywords: Adenosine receptor; Lipid raft; Caveola; Caveolin; Cholesterol
Recent developments in adenosine receptor ligands and their potential as novel drugs by Muller Christa E. Müller; Kenneth A. Jacobson (pp. 1290-1308).
Medicinal chemical approaches have been applied to all four of the adenosine receptor (AR) subtypes (A1, A2A, A2B, and A3) to create selective agonists and antagonists for each. The most recent class of selective AR ligands to be reported is the class of A2BAR agonists. The availability of these selective ligands has facilitated research on therapeutic applications of modulating the ARs and in some cases has provided clinical candidates. Prodrug approaches have been developed which improve the bioavailability of the drugs, reduce side-effects, and/or may lead to site-selective effects. The A2A agonist regadenoson (Lexiscan®), a diagnostic drug for myocardial perfusion imaging, is the first selective AR agonist to be approved. Other selective agonists and antagonists are or were undergoing clinical trials for a broad range of indications, including capadenoson and tecadenoson (A1 agonists) for atrial fibrillation, or paroxysmal supraventricular tachycardia, respectively, apadenoson and binodenoson (A2A agonists) for myocardial perfusion imaging, preladenant (A2A antagonist) for the treatment of Parkinson's disease, and CF101 and CF102 (A3 agonists) for inflammatory diseases and cancer, respectively. This article is part of a Special Issue entitled: “Adenosine Receptors”.► Potent, selective agonists and antagonists for all four AR subtypes have been developed. ► Prodrug approaches may lead to improved bioavailability. ► Regadenoson, an A2A-selective agonist was approved for myocardial perfusion imaging. ► Several adenosine receptor agonists and antagonists are currently evaluated in clinical trials. ► AR ligands are developed for CV, neurodegenerative and inflammatory diseases and cancer.
Keywords: Adenosine receptor; Agonist; Antagonist; Clinical trial; Medicinal chemistry; G protein-coupled receptor
Allosteric modulation of adenosine receptors by Goblyos Anikó Göblyös; Ad P. IJzerman (pp. 1309-1318).
Allosteric ligands for G protein-coupled receptors (GPCRs) may alter receptor conformations induced by an orthosteric ligand. These modulators can thus fine-tune classical pharmacological responses. In this review we will describe efforts to synthesize and characterize allosteric modulators for one particular GPCR subfamily, the adenosine receptors. There are four subtypes of these receptors: A1, A2A, A2B and A3. Allosteric enhancers for the adenosine A1 receptor may have anti-arrythmic and anti-lipolytic activity. They may also act as analgesics and neuroprotective agents. A3 allosteric enhancers are thought to be beneficial in ischemic conditions or as antitumor agents. We will summarize recent developments regarding the medicinal chemistry of such compounds. Most data have been and are published about the adenosine A1 and A3 receptor, whereas limited or no information is available for the A2A and A2B receptor, respectively. Receptor mutation studies are also discussed, as they may shed light on the localization of the allosteric binding sites. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: Abbreviations; AE; allosteric enhancer; 2-AG; 2-arachidonylglycerol; AR; adenosine receptor; cAMP; cyclic adenosine monophosphate; cDNA; complementary deoxyribonucleic acid; CCPA; 2-chloro-; N; 6; -cyclopentyladenosine; CGS21680; 2-[; p; -(2-carboxyethyl)phenyl-ethylamino]-5′-; N; -ethylcarboxamidoadenosine; CGS15943; 5-amino-9-chloro-2-(2-furyl)-1,2,4-triazolo[1,5-; c; ]quinazoline; CHO; Chinese hamster ovary; Cl-IB-MECA; 2-chloro-; N; 6; -(3-iodobenzyl)-5′-; N; -methylcarboxamidoadenosine; CB; cyclobutyl; CH; cyclohexyl; CP; cyclopentyl; DMA; 5-(; N; ,; N; -dimethyl)amiloride; DMF; dimethylformamide; DMSO; dimethylsulfoxide; DPCPX; 8-cyclopentyl-1,3-dipropylxanthine; DU 124183; 2-cyclopentyl-4-phenylamino-1; H; -imidazo[4,5-; c; ]quinoline; GPCR; G protein-coupled receptor; GTPγS; guanosine 5′-[γ-thio]triphosphate; h; human; HMA; 5-(; N; ,; N; -hexamethylene)amiloride; HPLC-MS; high performance liquid cromatogrphy-mass spectrometry; I-ABA; N; 6; -4-amino-3-iodo-benzyladenosine; I-AB-MECA; N; 6; -(4-amino-3-iodobenzyl)-5′-; N; -methylcarbamoyladenosine; LUF6000; N; -(3,4-dichlorophenyl)-2-cyclohexyl-1; H; -imidazo[4,5-; c; ]quinolin-4-amine; LUF6096; N; -{2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarboxamide; MRS1754; 8-(4-[{(4-cyanophenyl)carbamoylmethyl}oxy]phenyl)-1,3-di(; n; -propyl)xanthine; NECA; 5′-; N; -ethylcarboxamidoadenosine; PD 71,605; (2-amino-4,5,6,7-tetrahydro-benzo[; b; ]thiophen-3-yl)-(2-chloro-phenyl)-methanone; PD 117,975; (2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-; c; ]pyridin-3-yl)(4-chloro-phenyl)methanone; PD 81,723; 2-amino-4,5-dimethyl-3-thienyl-[3-(trifluoromethyl)phenyl]methanone; PSB603; 8-[4-[4-(4-chlorophenzyl)piperazine-1-sulfonyl)phenyl]]-1-propylxanthine; R-PIA; N; 6; -[(; R; )-phenylisopropyl]adenosine; SAR; structure–activity relationships; SCH-202676; (; N; -(2,3-diphenyl-[1,2,4]thiadiazole-5(2; H; )-ylidene)methanamine); T-62; (2-amino-4,5,6,7-tetrahydrobenzo[; b; ]thiophen-3-yl)-(4-chlorophenyl)-methanone; TM; transmembrane domain; VUF5455; 4-methoxy-; N; -[7-methyl-3-(2-pyridinyl)-1-isoquinolinyl]benzamide; VUF8502; 4-methyl-; N; -[3-(2-pyridinyl)-1-isoquinolinyl]benzamide; VUF8504; 4-methoxy-; N; -[3-(2-pyridinyl)-1-isoquinolinyl]benzamide; VUF8507; N; -[3-(2-pyridinyl)-1-isoquinolinyl]benzamide; ZM241385; 4-{2-[7-amino-2-(2-furyl)-1,2,4-triazolo[1,5-; a; ]1,3,5]triazin-5-yl-amino]ethyl}phenolAdenosine receptor; Allosteric modulation; Hybrid allo/orthosteric ligand; PD81,723; LUF5485; LUF6000; LUF6096
Adenosine receptor desensitization and trafficking by Stuart Mundell; Eamonn Kelly (pp. 1319-1328).
As with the majority of G-protein-coupled receptors, all four of the adenosine receptor subtypes are known to undergo agonist-induced regulation in the form of desensitization and trafficking. These processes can limit the ability of adenosine receptors to couple to intracellular signalling pathways and thus reduce the ability of adenosine receptor agonists as well as endogenous adenosine to produce cellular responses. In addition, since adenosine receptors couple to multiple signalling pathways, these pathways may desensitize differentially, while the desensitization of one pathway could even trigger signalling via another. Thus, the overall picture of adenosine receptor regulation can be complex. For all adenosine receptor subtypes, there is evidence to implicate arrestins in agonist-induced desensitization and trafficking, but there is also evidence for other possible forms of regulation, including second messenger-dependent kinase regulation, heterologous effects involving G proteins, and the involvement of non-clathrin trafficking pathways such as caveolae. In this review, the evidence implicating these mechanisms is summarized for each adenosine receptor subtype, and we also discuss those issues of adenosine receptor regulation that remain to be resolved as well as likely directions for future research in this field. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: Adenosine receptor; Desensitization; Internalization; Arrestin; Kinase
The resurgence of A2B adenosine receptor signaling by Carol M. Aherne; Emily M. Kewley; Holger K. Eltzschig (pp. 1329-1339).
Since its discovery as a low-affinity adenosine receptor (AR), the A2B receptor (A2BAR), has proven enigmatic in its function. The previous discovery of the A2AAR, which shares many similarities with the A2BAR but demonstrates significantly greater affinity for its endogenous ligand, led to the original perception that the A2BAR was not of substantial physiologic relevance. In addition, lack of specific pharmacological agents targeting the A2BAR made its initial characterization challenging. However, the importance of this receptor was reconsidered when it was observed that the A2BAR is highly transcriptionally regulated by factors implicated in inflammatory hypoxia. Moreover, the notion that during ischemia or inflammation extracellular adenosine is dramatically elevated to levels sufficient for A2BAR activation, indicated that A2BAR signaling may be important to dampen inflammation particularly during tissue hypoxia. In addition, the recent advent of techniques for murine genetic manipulation along with development of pharmacological agents with enhanced A2BAR specificity has provided invaluable tools for focused studies on the explicit role of A2BAR signaling in different disease models. Currently, studies performed with combined genetic and pharmacological approaches have demonstrated that A2BAR signaling plays a tissue protective role in many models of acute diseases e.g. myocardial ischemia, or acute lung injury. These studies indicate that the A2BAR is expressed on a wide variety of cell types and exerts tissue/cell specific effects. This is an important consideration for future studies where tissue or cell type specific targeting of the A2BAR may be used as therapeutic approach. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: Adenosine; A2BAR; Ischemia; Lung injury; Vascular injury; Inflammation; Hypoxia-inducible factor; HIF
Modulation of brain-derived neurotrophic factor (BDNF) actions in the nervous system by adenosine A2A receptors and the role of lipid rafts by Sebastiao Ana M. Sebastião; Natália Assaife-Lopes; Diogenes Maria J. Diógenes; Sandra H. Vaz; Joaquim A. Ribeiro (pp. 1340-1349).
In this paper we review some novel aspects related to the way adenosine A2A receptors (A2AR) modulate the action of BDNF or its high-affinity receptors, the TrkB receptors, on synaptic transmission and plasticity, as well as upon cholinergic currents and GABA transporters. Evidence has been accumulating that adenosine A2ARs are required for most of the synaptic actions of BDNF. In some cases, where A2ARs are constitutively activated (e.g. by endogenous extracellular adenosine), the need for A2AR activation for the maintenance of the synaptic influences of BDNF can be envisaged from the loss of BDNF effects upon blockade of adenosine A2ARs or upon removal of extracellular adenosine with adenosine deaminase. In some other cases, it is necessary to enhance extracellular adenosine levels (e.g. depolarization) or to further activate A2ARs (e.g. with selective agonists) to trigger a BDNF neuromodulatory role at the synapses. Age- and cell-dependent differences may determine the above two possibilities, but in all cases it is quite clear that there is close interplay between adenosine A2ARs and BDNF TrkB receptors at synapses. The role of lipid rafts in this cross-talk will be discussed. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: Adenosine A; 2A; receptors; BDNF; Lipid rafts; TrkB receptors; Receptor–receptor cross talk; Adenosine neuromodulation; Synaptic transmission
From cradle to twilight: The carboxyl terminus directs the fate of the A2A-adenosine receptor by Simon Keuerleber; Ingrid Gsandtner; Michael Freissmuth (pp. 1350-1357).
The extended carboxyl terminus of the A2A-adenosine receptor is known to engage several proteins other than those canonically involved in signalling by GPCRs (i.e., G proteins, G protein-coupled receptor kinases/GRKs, arrestins). The list includes the deubiquinating enzyme USP4, α-actinin, the guanine nucleotide exchange factor for ARF6 ARNO, translin-X-associated protein, calmodulin, the neuronal calcium binding protein NECAB2 and the synapse associated protein SAP102. However, if the fate of the A2A-receptor is taken into account — from its birthplace in the endoplasmic reticulum to its presumed site of disposal in the lysosome, it is evident that many more proteins must interact with the A2A-adenosine receptor. There are several arguments that support the conjecture that these interactions will preferentially occur with the carboxyl terminus of the A2A-adeonsine receptor: (i) the extended carboxyl terminus (of 122 residues=) offers the required space to accommodate companions; (ii) analogies can be drawn with other receptors, which engage several of these binding partners with their C-termini. This approach allows for defining the nature of the unknown territory. As an example, we posit a chaperone/coat protein complex-II (COPII) exchange model that must occur on the carboxyl terminus of the receptor. This model accounts for the observation that a minimum size of the C-terminus is required for correct folding of the receptor. It also precludes premature recruitment of the COPII-coat to a partially folded receptor. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: A; 2A; -adenosine receptor; G; s; ARNO; ARF6; USP4; C-terminus; ER export
Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies by Catherine J. Wei; Wei Li; Jiang-Fan Chen (pp. 1358-1379).
Endogenous adenosine is a widely distributed upstream regulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways that converge to contribute to the expression of an array of important brain functions. Over the past decade, the generation and characterization of genetic knockout models for all four G-protein coupled adenosine receptors, the A1 and A2A receptors in particular, has confirmed and extended the neuromodulatory and integrated role of adenosine receptors in the control of a broad spectrum of normal and abnormal brain functions. After a brief introduction of the available adenosine receptor knockout models, this review focuses on findings from the genetic knockout approach, placing particular emphasis on the most recent findings. This review is organized into two sections to separately address (i) the role of adenosine receptors in normal brain processes including neuroplasticity, sleep–wake cycle, motor function, cognition, and emotion-related behaviors; and (ii) their role in the response to various pathologic insults to brain such as ischemic stroke, neurodegeneration, or brain dysfunction/disorders. We largely limit our overview to the prominent adenosine receptor subtypes in brain–the A1 and A2A receptors–for which numerous genetic knockout studies on brain function are available. A1 and A2A receptor knockouts have provided significant new insights into adenosine's control of complex physiologic (e.g., cognition) and pathologic (e.g., neuroinflammation) phenomena. These findings extend and strengthen the support for A1 and A2A receptors in brain as therapeutic targets in several neurologic and psychiatric diseases. However, they also emphasize the importance of considering the disease context-dependent effect when developing adenosine receptor-based therapeutic strategies. This article is part of a Special Issue entitled: “Adenosine Receptors”.► ARs integrate and fine-tune multiple neurotransmitters and CNS signaling pathways. ► Striatal A2AR activity is critical for habit learning and cognitive control. ► AR-effects depend on the local brain pathology and timing of intervention. ► A2ARs represent important targets for neuropsychiatric diseases. ► AR-based drugs may need to be tailored to the specific disease process.
Keywords: Adenosine; Adenosine receptors; A1 receptor, A2A receptor, knockout; Neuroprotection; Cognition; Neuroinflammation
Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration by Catarina V. Gomes; Manuella P. Kaster; Tome Angelo R. Tomé; Paula M. Agostinho; Rodrigo A. Cunha (pp. 1380-1399).
Adenosine acts in parallel as a neuromodulator and as a homeostatic modulator in the central nervous system. Its neuromodulatory role relies on a balanced activation of inhibitory A1 receptors (A1R) and facilitatory A2A receptors (A2AR), mostly controlling excitatory glutamatergic synapses: A1R impose a tonic brake on excitatory transmission, whereas A2AR are selectively engaged to promote synaptic plasticity phenomena. This neuromodulatory role of adenosine is strikingly similar to the role of adenosine in the control of brain disorders; thus, A1R mostly act as a hurdle that needs to be overcame to begin neurodegeneration and, accordingly, A1R only effectively control neurodegeneration if activated in the temporal vicinity of brain insults; in contrast, the blockade of A2AR alleviates the long-term burden of brain disorders in different neurodegenerative conditions such as ischemia, epilepsy, Parkinson's or Alzheimer's disease and also seem to afford benefits in some psychiatric conditions. In spite of this qualitative agreement between neuromodulation and neuroprotection by A1R and A2AR, it is still unclear if the role of A1R and A2AR in the control of neuroprotection is mostly due to the control of glutamatergic transmission, or if it is instead due to the different homeostatic roles of these receptors related with the control of metabolism, of neuron–glia communication, of neuroinflammation, of neurogenesis or of the control of action of growth factors. In spite of this current mechanistic uncertainty, it seems evident that targeting adenosine receptors might indeed constitute a novel strategy to control the demise of different neurological and psychiatric disorders. This article is part of a Special Issue entitled: “Adenosine Receptors”.► Bolstering the effects of adenosine A1 receptors affords neuroprotection. ► Blocking the effects of adenosine A2A receptors affords neuroprotection. ► Chronic consumption of caffeine affords neuroprotection.
Keywords: Adenosine; Caffeine; Neurodegeneration; Ischemia; Epilepsy; Alzheimer's disease; Growth factors; Neurogenesis
Adenosine receptors and cancer by Stefania Gessi; Stefania Merighi; Valeria Sacchetto; Carolina Simioni; Pier Andrea Borea (pp. 1400-1412).
Adenosine is a ubiquitous signaling molecule whose physiological functions are mediated by its interaction with four G-protein-coupled receptor subtypes, termed A1, A2A, A2B and A3. As a result of increased metabolic rates, this nucleoside is released from a variety of cells throughout the body in concentrations that can have a profound impact on vasculature and immunoescape. However, as high concentrations of adenosine have been reported in cancer tissues, it also appears to be implicated in the growth of tumors. Thus, full characterisation of the role of adenosine in tumor development, by addressing the question of whether adenosine receptors are present in cancer tissues, and, if so, which receptor subtype mediates its effects in cancer growth, is a vital research goal. To this end, this review focuses on the most relevant aspects of adenosine receptor subtype activation in tumors reported so far. Although all adenosine receptors now have an increasing number of recognised biological roles in tumors, it seems that the A2A and A3 subtypes are the most promising as regards drug development. In particular, activation of A2A receptors leads to immunosuppressive effects, which decreases anti-tumoral immunity and thereby encourages tumor growth. Due to this behavior, the addition of A2A antagonists to cancer immunotherapeutic protocols has been suggested as a way of enhancing tumor immunotherapy. Interestingly, the safety of such compounds has already been demonstrated in trials employing A2A antagonists in the treatment of Parkinson's disease. As for A3 receptors, the effectiveness of their agonists in several animal tumor models has led to the introduction of these molecules into a programme of pre-clinical and clinical trials. Paradoxically, A3 receptor antagonists also appear to be promising candidates in human cancer treatment of regimes. Clearly, research in this still field is still in its infancy, with several important and challenging issues remaining to be addressed, although purine scientists do seem to be getting closer to their goal: the incorporation of adenosine ligands into drugs with the ability to save lives and improve human health. This article is part of a Special Issue entitled: “Adenosine Receptors”.► Adenosine receptors play contrasting effects in tumor cell growth. ► A3 receptors are overexpressed in cancer tissues and cells. ► A2A antagonists enhance immunotherapy of tumors. ► A3 agonists reduce cancer growth by inhibiting cell proliferation. ► A3 antagonists inhibit cancer development by blocking HIF-1α accumulation.
Keywords: A; 1; adenosine receptor; A; 2A; adenosine receptor; A; 2B; adenosine receptor; A; 3; adenosine receptor; Cancer; Molecular mechanism
Adenosine and its receptors in the heart: Regulation, retaliation and adaptation by John P. Headrick; Jason N. Peart; Melissa E. Reichelt; Luke J. Haseler (pp. 1413-1428).
The purine nucleoside adenosine is an important regulator within the cardiovascular system, and throughout the body. Released in response to perturbations in energy state, among other stimuli, local adenosine interacts with 4 adenosine receptor sub-types on constituent cardiac and vascular cells: A1, A2A, A2B, and A3ARs. These G-protein coupled receptors mediate varied responses, from modulation of coronary flow, heart rate and contraction, to cardioprotection, inflammatory regulation, and control of cell growth and tissue remodeling. Research also unveils an increasingly complex interplay between members of the adenosine receptor family, and with other receptor groups. Given generally favorable effects of adenosine receptor activity ( e.g. improving the balance between myocardial energy utilization and supply, limiting injury and adverse remodeling, suppressing inflammation), the adenosine receptor system is an attractive target for therapeutic manipulation. Cardiovascular adenosine receptor-based therapies are already in place, and trials of new treatments underway. Although the complex interplay between adenosine receptors and other receptors, and their wide distribution and functions, pose challenges to implementation of site/target specific cardiovascular therapy, the potential of adenosinergic pharmacotherapy can be more fully realized with greater understanding of the roles of adenosine receptors under physiological and pathological conditions. This review addresses some of the major known and proposed actions of adenosine and adenosine receptors in the heart and vessels, focusing on the ability of the adenosine receptor system to regulate cell function, retaliate against injurious stressors, and mediate longer-term adaptive responses.
Keywords: Abbreviations; AR; adenosine receptor; ANP; atrial natriuretic peptide; AV; atrioventricular; ECM; extracellular matrix; E; pac; exchange protein directly activated by cAMP; FFA; free fatty acid; GPCR; G-protein coupled receptor; HIF; hypoxia inducible factor; HSP; heat shock protein; IFN; interferon; IL-; interleukin; K; ATP; ATP-gated K; +; channel; MAPK; mitogen-activated protein kinase; MMP; matrix metalloproteinase; NHE; Na; +; /H; +; exchanger; NO; nitric oxide; PI3K; phosphoinositide 3-kinase; P; i; inorganic phosphate; PKC; protein kinase C; PLC; phospholipase C; PostC; postconditioning; PreC; preconditioning; ROS; reactive oxygen species; SA; sinoatrial; 8-PT; 8-phenyltheophylline; STEMI; ST-segment elevation myocardial infarction; TNF-α; tumor necrosis factor α; VEGF; vascular endothelial growth factorAdenosine; Adenosine receptor; Angiogenesis; Atherosclerosis; Cardioprotection; Contractility; Glycolysis; Heart rate; Hypertrophy; Inflammation; Infarction; Ischemia-reperfusion; Preconditioning; Postconditioning; Remodeling; Vasculogenesis
Adenosine receptors and vascular inflammation by Dovenia S. Ponnoth; S. Jamal Mustafa (pp. 1429-1434).
Epidemiological studies have shown a positive correlation between poor lung function and respiratory disorders like asthma and the development of adverse cardiovascular events. Increased adenosine (AD) levels are associated with lung inflammation which could lead to altered vascular responses and systemic inflammation. There is relatively little known about the cardiovascular effects of adenosine in a model of allergy. We have shown that A1 adenosine receptors (AR) are involved in altered vascular responses and vascular inflammation in allergic mice. Allergic A1wild-type mice showed altered vascular reactivity, increased airway responsiveness and systemic inflammation. Our data suggests that A1 AR is pro-inflammatory systemically in this model of asthma. There are also reports of the A2B receptor having anti-inflammatory effects in vascular stress; however its role in allergy with respect to vascular effects hasn't been fully explored. In this review, we have focused on the role of adenosine receptors in allergic asthma and the cardiovascular system and possible mechanism(s) of action. This article is part of a Special Issue entitled: “Adenosine Receptors”.
Keywords: Abbreviations; AC; Adenylyl cyclase; ACh; Acetylcholine; ADA; Adenosine deaminase; AD; Adenosine; ADP; Adenosine diphosphate; AR; Adenosine receptor; AK; Adenosine kinase; AMP; Adenosine monophosphate; BAL; Bronchoalveolar lavage; cAMP; Cyclic adenosine monophosphate; CCPA; 2-chloro-N6-cyclopentyladenosine; CGS 21860; 2-; p; -(2-carboxyethyl)phenethylamino-5′ N-ethylcarboxy amidoadenosine hydrochloride; COPD; Chronic obstructive pulmonary disease; CV; Cardiovascular; CVD; Cardiovascular disease; DAG; Diacylglycerol; DPCPX; 1,3-Dipropyl-8-cyclopentylxanthine; IP; 3; Inositol triphosphate; LO; Lipoxygenase; LT; Leukotriene; KO; Knockout; NECA; N-ethylcarboxamide-adenosine; SAH; S-Adenosyl-L-homocysteine; SAH-hydrolase; S-Adenosyl-L-homocysteine-hydrolase; SAM; S-Adenosyl-L-methionine; WT; Wild typeAllergy; Asthma; Vascular inflammation; Vascular reactivity; Adenosine receptors; Adenosine metabolism; G-protein coupled receptor