Cafeína y función biológica de los receptores de adenosina

About thirty years ago it was realized that caffeine, the most widely used of all psychoactive drugs, is able to antagonize the effects of adenosine at concentrations achieved during normal human consumption. This finding had several important implications: 1) there are receptors at which adenosine is the agonist and caffeine the antagonist; 2) since the antagonist is biologically active it should mean that the receptors are activated by endogenous adenosine. This brief overview, which reflects the contents of my introductory lecture at the Academy, will present some data vindicating these conclusions. The metabolism of adenosine and its levels under normal and pathophysiological conditions has been elucidated. Now four different adenosine receptors have been cloned and pharmacologically characterized. They are all G protein coupled. Their different signalling characteristics are briefly summarized as is their distribution. Based on these data t is concluded that caffeine probably exerts its effects by blocking adenosine A1 and A2A receptors. The biological role(s) of these receptors is finally presented using data from knock-out mice.Hace aproximadamente 30 años se descubrió que la cafeína, la más empleada de todas las substancias psico-estimulantes, es capaz de antagonizar los efectos de la adenosina a concentraciones que se alcanzan durante el consumo normal de café y otros alimentos ó bebidas. Este descubrimiento tiene varias consecuencias importantes: 1) existen receptores para los cuales la adenosina es el agonista y la cafeína el antagonista; 2) Ya que el antagonista es biológicamente activo, los receptores deben de estar activados por la adenosina endógena. Esta breve visión de conjunto, la cual refleja el contenido del Discurso de Entrada en la Real Academia de Farmacia del Profesor B. Fredholm, presentará los datos que avalan las conclusiones previamente enunciadas. El metabolismo de la adenosina y sus niveles en condiciones normales y fisiopatológicas es conocido con detalle. Actualmente han sido clonados y caracterizado farmacologicamente cuatro receptores de adenosina. Todos ellos están acoplados a proteínas G y tienen cascadas de señalización y distribuciones diversas en el organismo. Es probable que los efectos biológicos de la cafeína se realicen mayoritariamente a través de receptores A1 y A2A. Los datos obtenidos con ratones genéticamente modificados, anulando estos genes confirma su función biológica

Perinatal Caffeine, Acting on Maternal Adenosine A1 Receptors, Causes Long-Lasting Behavioral Changes in Mouse Offspring

Background: There are lingering concerns about caffeine consumption during pregnancy or the early postnatal period, partly because there may be long-lasting behavioral changes after caffeine exposure early in life. Methodology/Principal Findings: We show that pregnant wild type (WT) mice given modest doses of caffeine (0.3 g/l in drinking water) gave birth to offspring that as adults exhibited increased locomotor activity in an open field. The offspring also responded to cocaine challenge with greater locomotor activity than mice not perinatally exposed to caffeine. We performed the same behavioral experiments on mice heterozygous for adenosine A 1 receptor gene (A 1RHz). In these mice signaling via adenosine A1 receptors is reduced to about the same degree as after modest consumption of caffeine. A1RHz mice had a behavioral profile similar to WT mice perinatally exposed to caffeine. Furthermore, it appeared that the mother’s genotype, not offspring’s, was critical for behavioral changes in adult offspring. Thus, if the mother partially lacked A1 receptors the offspring displayed more hyperactivity and responded more strongly to cocaine stimulation as adults than did mice of a WT mother, regardless of their genotype. This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus. WT offspring from WT mother but having a A1R Hz grandmother preserved higher locomotor response to cocaine. Conclusions/Significance: We suggest that perinatal caffeine, by acting on adenosine A 1 receptors in the mother, cause

Pharmacological targeting of adenosine receptor signaling

Adenosine receptor signaling plays important roles in normal physiology, but is also known to modulate the development or progression of several different diseases. The design of new, efficient, and safe pharmacological approaches to target the adenosine system may have considerable therapeutic potential, but is also associated with many challenges. This review summarizes the main challenges of adenosine receptor targeted treatment including tolerance, disease stage, cell type-specific effects, caffeine intake, adenosine level assessment and receptor distribution in vivo. Moreover, we discuss several potential ways to overcome these obstacles (i.e., the use of partial agonists, indirect receptor targeting, allosteric enhancers, prodrugs, non-receptor-mediated effects, neoreceptors, conditional knockouts). It is important to address these concerns during development of new and successful therapeutic approaches targeting the adenosine system

Adenosine induces airway hyperresponsiveness through activation of A3 receptors on mast cells

The mechanisms responsible for the development of airway hyperresponsiveness in asthma are poorly understood. Adenosine levels are high in the lungs of patients with asthma, but a role for adenosine in the development of this cardinal feature of asthma has not been previously reported

Adenosine receptors in GtoPdb v.2021.2

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [110]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [153, 313, 221, 61], agonist-bound [375, 203, 204] and G protein-bound A2A adenosine receptors [49] have been described. The structures of an antagonist-bound A1 receptor [128] and an adenosine-bound A1 receptor-Gi complex [86] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [57]. caffeine is a nonselective antagonist for adenosine receptors, while istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson's disease

Adenosine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [103]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [146, 305, 213, 55], agonist-bound [362, 196, 198] and G protein-bound A2A adenosine receptors [43] have been described. The structures of an antagonist-bound A1 receptor [123] and an adenosine-bound A1 receptor-Gi complex [80] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [51]

Adenosine receptors in GtoPdb v.2023.1

Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [112]) are activated by the endogenous ligand adenosine (potentially inosine also at A3 receptors). Crystal structures for the antagonist-bound [155, 316, 224, 62], agonist-bound [379, 205, 206] and G protein-bound A2A adenosine receptors [49] have been described. The structures of an antagonist-bound A1 receptor [130] and an adenosine-bound A1 receptor-Gi complex [87] have been resolved by cryo-electronmicroscopy. Another structure of an antagonist-bound A1 receptor obtained with X-ray crystallography has also been reported [58]. The structure of the A2B receptor has also been elucidated [57]. caffeine is a nonselective antagonist for adenosine receptors, while istradefylline, a selective A2A receptor antagonist, is on the market for the treatment of Parkinson's disease