Adenosine receptors

Thank you for visiting nature. You are using a browser version with limited support for CSS.

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. Adenosine is a key endogenous molecule that is released from cells and regulates tissue function via activating four G-protein-coupled adenosine receptors: A 1 , A 2A , A 2B and A 3. These receptors are abundantly expressed on the surface of immune cells as well as on endothelial, smooth muscle, epithelial cells, fibroblasts and cardiomyocytes.

Adenosine receptors

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. This review documents the present state of knowledge of the contribution of AR, particularly A 1 and A 2A , to psychostimulants-mediated effects, including locomotor activity, discrimination, seeking and reward, and discuss their therapeutic relevance to psychostimulant addiction. Studies presented in this review reinforce the potential of A 1 agonists as an effective strategy to counteract psychostimulant-induced effects. The overall analysis of presented data provide evidence that excitatory modulation of A 1 and A 2A receptors constitute promising tools to counteract psychostimulants addiction. Drug addiction is a complex chronic cognitive disorder characterized by drug seeking and compulsive use, which is difficult to control despite its harmful consequences. According to DSM-5 American Psychiatric Association, , which is used to define mental disorders in epidemiologic studies, it is now accepted that the criteria used to clinically define the terms abuse and dependence should be combined to form a new category known as Substance use disorders , including craving as a new criterion to increase diagnostic accuracy Hasin et al. In terms of epidemiology, drug addiction is currently a global health problem, as can be deduced from comparison of data obtained from the Global Burden of Diseases Study between and For the period —, global exposure to drug use increased by In addition, by drug use was a major risk factor for early death and disability in developed countries like the United States, Canada, Australia, and the United Kingdom, being the 5th leading global risk factor for men and the 12th for women GBD Risk Factors Collaborators,

Rybak L. Kuzmin, A.

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.

Adenosine, beside its role in the intermediate metabolism, mediates its physiological functions by interacting with four receptor subtypes named A 1 , A 2A , A 2B and A 3. All these receptors belong to the superfamily of G protein-coupled receptors that represent the most widely targeted pharmacological protein class. Since adenosine receptors are widespread throughout the body, they are involved in a variety of physiological processes and pathology including neurological, cardiovascular, inflammatory diseases and cancer. At now, it is ascertained that the biological responses evoked by the activation of a single receptor are the result of complex and integrated signalling pathways targeted by different receptor proteins, interacting each other. These pathways may in turn control receptor responsiveness over time through fine regulatory mechanisms including desensitization-internalization processes. The knowledge of adenosine receptor structure as well as the molecular mechanisms underlying the regulation of receptor functioning and of receptor-receptor interactions during physio and pathological conditions represent a pivotal starting point to the development of new drugs with high efficacy and selectivity for each adenosine receptor subtype. The goal of this review is to summarize what we now and what we are learning about adenosine receptor structure, signalling and regulatory mechanisms. In addition, to dissect the potential therapeutic application of adenosine receptor ligands, the pathophysiological role of the receptor subtypes in different tissues are discussed. Abstract Adenosine, beside its role in the intermediate metabolism, mediates its physiological functions by interacting with four receptor subtypes named A 1 , A 2A , A 2B and A 3. Publication types Review.

Adenosine receptors

Nucleoside transporters. The adenosine receptors or P1 receptors [1] are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. The adenosine receptors are commonly known for their antagonists caffeine , theobromine , and theophylline , whose action on the receptors produces the stimulating effects of coffee , tea and chocolate. Each type of adenosine receptor has different functions, although with some overlap. Most older compounds acting on adenosine receptors are nonselective, with the endogenous agonist adenosine being used in hospitals as treatment for severe tachycardia rapid heart beat , [9] and acting directly to slow the heart through action on all four adenosine receptors in heart tissue, [10] as well as producing a sedative effect through action on A 1 and A 2A receptors in the brain. Xanthine derivatives such as caffeine and theophylline act as non-selective antagonists at A 1 and A 2A receptors in both heart and brain and so have the opposite effect to adenosine, producing a stimulant effect and rapid heart rate.

Take that on radio 2

Increased nociceptive response in mice lacking the adenosine A1 receptor. Different roles of adenosine A1, A2A and A3 receptors in controlling kainate-induced toxicity in cortical cultured neurons. Ciancetta, A. Integrative scheme of reward circuit in striatum with focus on adenosine and dopamine receptors and their interactions. Stone, T. Phillips, K. Guo, Y. USA 88 , — An enprofylline-sensitive mechanism with implications for asthma. The N -terminal domain has N -glycosylation sites which influences trafficking of the receptor to the plasma membrane [ 17 , 18 ]. Expression of A1 adenosine receptors in the developing avian retina: In vivo modulation by A 2A receptors and endogenous adenosine. A3 adenosine receptors: novel ligands and paradoxical effects. In this model a heterologous pattern of desensitization is apparent and regulation of multiple components of the system occurs. Figure 4: A 2B receptor activation has broad pro-inflammatory actions by stimulating the pro-inflammatory functions of a variety of cell types that mediate asthma. Adenosine affects several functions in the body, exerting its physiological effects through regulation of four G-protein coupled receptors GPCRs named A 1 , A 2A , A 2B , and A 3 , characterized by different affinities for adenosine, tissue distribution, and coupling with effector systems.

Adenosine is a naturally occurring nucleoside that is distributed ubiquitously throughout the body as a metabolic intermediary.

A 1 and A 3 adenosine receptors inhibit LPS-induced hypoxia-inducible factor-1 accumulation in murine astrocytes. As for psychostimulants-induced changes in AR expression in brain areas only few scientific reports have been reported. Moreover, mutation of two palmitoylation sites within the carboxy-terminus, Cys and Cys of rat A 3 AR which controls the GRK phosphorylation sites, displayed a significant level of basal phosphorylation even in the absence of an agonist. Ledent, C. Neurology 61 , S—S Gessi, S. Cell Physiol. Small 2-substitutions, such as 2-CADO 22 tend towards relative nonselectivity or modest A 2 selectivity. It is clear, however, that the activation of G proteins by receptors is dependent on the presence of GTP and leads to the activation or inhibition of the effector system such as adenylate cyclase or phospholipases. Moro, S. For example, CPPIQA 73 , which conforms with the required EP distribution and which has two hydrophobic substituents at the appropriate sites a 2-phenyl and a 4-cyclopentyl group , has an affinity of 1. Expression and function of adenosine receptors in the chinchilla cochlea. It appears that both agonist and antagonist photoaffinity labeling of A 1 receptors occurs in the same region of the peptide sequence of the receptor. Maier, L.