Adenosine receptors

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Adenosine receptors AR are a family of G-protein coupled receptors, comprised of four members, named A 1 , A 2A , A 2B , and A 3 receptors, found widely distributed in almost all human body tissues and organs. To date, they are known to participate in a large variety of physiopathological responses, which include vasodilation, pain, and inflammation. In particular, in the central nervous system CNS , adenosine acts as a neuromodulator, exerting different functions depending on the type of AR and consequent cellular signaling involved. In the CNS, A 1 receptors are widely distributed in the cortex, hippocampus, and cerebellum, A 2A receptors are localized mainly in the striatum and olfactory bulb, while A 2B and A 3 receptors are found at low levels of expression. In addition, AR are able to form heteromers, both among themselves e. Nowadays, we know that adenosine, by acting on adenosine A 1 and A 2A receptors, is known to antagonistically modulate dopaminergic neurotransmission and therefore reward systems, being A 1 receptors colocalized in heteromeric complexes with D 1 receptors, and A 2A receptors with D 2 receptors.

Adenosine receptors

Federal government websites often end in. The site is secure. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. This review will describe the biochemical characteristics and signaling cascade associated with each receptor and provide insight into how these receptors are regulated in response to agonists. Recent observations of oligomerization of these receptors into homo- and heterodimers will be discussed. In addition, the importance of these receptors in the regulation of normal and pathological processes such as sleep, the development of cancers and in protection against hearing loss will be examined. Adenosine is produced primarily from the metabolism of adenosine triphosphate ATP and exerts pleiotropic functions throughout the body. In the central nervous system CNS , adenosine plays important functions such as modulation of neurotransmitter release [ 1 ], synaptic plasticity [ 2 ] and neuroprotection in ischemic, hypoxic and oxidative stress events [ 3 — 5 ]. In addition, adenosine plays different roles in a large variety of tissues. In the cardiovascular system, adenosine produces either vasoconstriction or vasodilation of veins and arteries [ 6 ]. Adenosine regulates T cell proliferation and cytokine production [ 7 ]. The nucleoside also inhibits lipolysis and stimulates bronchoconstriction [ 8 , 9 ]. Adenosine is produced both intracellularly and extracellularly. It can be metabolized to inosine and hypoxanthine by adenosine deaminase and to uric acid by xanthine oxidase.

It has been suggested by Olsson that N 6 and C2 substituents of adenosine receptors derivatives may partly occupy the same receptor domain, adenosine receptors. Studies presented in this review reinforce the potential of A 1 agonists as an effective strategy to counteract psychostimulant-induced effects.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Modulation of adenosine receptors ARs using selective agonists and antagonists is a promising therapeutic strategy for the treatment of diseases and disorders of the cardiovascular, renal and nervous systems, as well as endocrine and pulmonary disorders. Although the development of novel AR ligands has therefore been the focus of much research, so far none has been approved for clinical use, in part owing to the ubiquity of ARs and the consequent possibility of side effects. However, there has been a recent impetus towards novel clinical targets, stimulated by the discovery and elucidation of the roles of the various AR subtypes and adenosine.

Adenosine is a naturally occurring nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary. In the brain, adenosine functions as an important upstream neuromodulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways. By acting through four G-protein-coupled receptors, adenosine contributes critically to homeostasis and neuromodulatory control of a variety of normal and abnormal brain functions, ranging from synaptic plasticity, to cognition, to sleep, to motor activity to neuroinflammation, and cell death. This review begun with an overview of the gene and genome structure and the expression pattern of adenosine receptors ARs. We feature several new developments over the past decade in our understanding of AR functions in the brain, with special focus on the identification and characterization of canonical and noncanonical signaling pathways of ARs. We provide an update on functional insights from complementary genetic-knockout and pharmacological studies on the AR control of various brain functions. We also highlight several novel and recent developments of AR neurobiology, including i recent breakthrough in high resolution of three-dimension structure of adenosine A2A receptors A2ARs in several functional status, ii receptor-receptor heterodimerization, iii AR function in glial cells, and iv the druggability of AR.

Adenosine receptors

Adenosine receptors A 1 , A 2A , A 2B , and A 3 are effector proteins triggered by the endogenous nucleoside adenosine to exert its numerous vital physiological effects, behaving like a guardian angel. This chapter offers an overview of the updated knowledge concerning the structure, distribution, and signal transduction of adenosine receptors. They are a family of G protein-coupled receptors widely distributed through the body, from central nervous system to peripheral organs, important and ubiquitous regulators of numerous cellular signaling. Their presence on every cell renders them an attractive opportunity for the pharmacological research and development of new drugs but also a challenge in the difficulty to produce tissue-selective ligands avoided of side effects. To aid this process, several efforts have been invested to reveal the molecular structure and the consequent mechanism of ligand binding of these receptors, and until now more than 30 structures have been published for the human A 2A subtype. Finally, the principal adenosine receptor signaling pathways including adenylyl cyclase, phospholipase C, inositol triphosphate, diacylglycerol, phosphatidylinositol 3-kinase, and mitogen-activated protein kinases determining their effects on several transcription factors, such as hypoxia-inducible factor 1, cyclic AMP cAMP -responsive elements, nuclear factor-kB, and exchange protein directly activated by cAMP as the most relevant, are presented. This is a preview of subscription content, log in via an institution. Biochim Biophys Acta Biomembr — J Biol Chem —

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The first and last residues of a helix are indicated by either i in; Le. All four subtypes are members of the superfamily of G-protein-coupled receptors, and each of these ARs has a unique pharmacological profile, tissue distribution and effector coupling. Yan, L. Nevertheless, the pattern is common in G-protein-linked receptors but is not found in other proteins, and hence it is very likely that this receptor domain is important for interaction with G proteins. Schindler, C. Harper, L. PubMed Abstract Google Scholar. Greengard P, Robison GA, editors. Cross-talk between cyclic AMP and protein kinase C pathways. Sulfur substitution of O 6 decreases affinity, whereas substitution of O 2 has little effect, 86 suggesting that the latter carbonyl oxygen is probably not involved in a hydrogen bond with the receptor, since sulfur is a very weak hydrogen bond acceptor.

Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A 1 , A 2A , A 2B , and A 3.

On the role of adenosine A 2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats. Wells, L. Unlike vesicular release of neurotransmitters upon electrical impulse, the release of adenosine is mediated mainly by the action of its transporters. Adenosine-dopamine interactions in the pathophysiology and treatment of CNS disorders. Selective A2A adenosine receptor activation reduces skin pressure ulcer formation and inflammation. Socodato R. Birkhauser; Basel: Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Adenosine deaminase irreversibly deaminates adenosine, converting it to the related nucleoside inosine by the removal of an amino group. Thirdly, due to the lack of information concerning the effects consequent to alcohol and psychostimulant co-abuse, which is very common in drug addiction Althobaiti and Sari, ; Barrett et al. The third stage, craving, depends on the prefrontal cortex, amygdala and hippocampus, and glutamate is the major neurotransmitter involved reviewed in Kelley and Berridge, ; Koob and Volkow, ; Kim et al. This circuitry is associated with the three stages of the addiction cycle Koob and Volkow,