[...]... role for A1 /A3 receptors is that the augmented response to adenosine was abolished when parenchymal strips were prepared from lungs removed from pertussis toxin-treated animals which had been 1  From Hypertension (+) to Asthma 21 challenged with antigen Pertussis toxin-sensitive G proteins include the Gi and Go families and are involved in the signalling pathways linked to A1 and A3 receptors (Fredholm... response to the prototype A3 receptor agonist, 2-Cl-IB-MECA, in the rat indicating that blockade of the A3 receptor could be obtained in vivo 1.4.3  Example of the Species Selectivity of the A3 Receptor: An The Receptor Responsible for Adenosine Augmentation of Mediator Release from Human Mast Cells Is Not the A3 Receptor At about the time that the efforts of the chemists to synthesise selective A3 antagonists... asthma • Adenosine facilitates preformed mediator and possibly cytokine release from mast cells by activating A3 receptors • Antagonists at the A3 receptor would prevent periodic exacerbations of asthma and lead over the longer term to a reduction in airways inflammation and bronchial hyperresponsiveness With this brief, our chemistry colleagues set out to design antagonists with potency and selectivity... R226, was identical to tgpcr1 (Zhou et al 1992) On the basis of the sequence homology in its transmembrane domains with the adenosine A1 (58%) and A2A (57%) receptors and its capacity to bind adenosine receptor agonist ligands, Zhou and colleagues concluded that R226 encoded an adenosine receptor which they designated the A3 receptor They confirmed the high expression of the receptor in the testis but,... response to adenosine was resistant to blockade by each of these compounds (Wolber and Fozard 2005) 1.6.2  2-Cl-IB-MECA Is a Silent Antagonist of the Mast Cell- Dependent Component of the Response to Adenosine and Reveals a Contribution to the Contractile Response from the A3 Receptor An abundant literature implicates the A3 receptor in the activation/degranulation of rat mast cells induced by adenosine. .. respect to the A3 receptor than the A2A or A2B receptors (Carruthers and Fozard 1993b; Fozard and Carruthers 1993a, b) Although at the time it was not known whether the human mast cell responded to A3 receptor stimulation with degranulation, it was recognized that a highly selective A1 receptor agonist may be needed to avoid a potentially 1  From Hypertension (+) to Asthma 7 dangerous activation and degranulation... significant activity at the (rat) A3 receptor is a widespread property amongst adenosine receptor ligands traditionally used to discriminate between adenosine A1 and A2 receptor subtypes and suggest prudence in the use of these agents as pharmacological tools 1.4  Antagonists of the A3 Receptor for the Treatment of Asthma 1.4.1  Background and Concept In 1994, I took over the leadership of the asthma... pig we identified a remarkable potentiation of the bronchoconstrictor response to allergen by activation of A3 receptors (Fig. 1.1) Together these findings spawned a concept, ‘The response of the airway mast cells to allergen is determined by adenosine acting through A3 receptors and, in 1995, a programme, ‘Antagonists of the A3 receptor for the treatment of asthma’, was initiated based on the following... (Wolber and Fozard 2005) (We were careful to verify that the contractile response to inosine was mediated largely by 5-HT released from mast cells as a result of activation of A3 receptors – Wolber and Fozard 2005) This result led us to consider the possibility that 2-Cl-IB-MECA might be an antagonist at the site (probably the A3 receptor) mediating the mast cell- dependent contractile response to adenosine. .. with A3 receptor agonists are likely to reflect the polypharmacology of A3 receptor activation plus the effects of the mediators released from mast cells Importantly, such data would be of limited relevance, if any, to the human where the A3 receptor appears to play no role in mast cell degranulation (Gessi et al 2008; Hasko et al 2008; Wilson 2008) Finally, we showed that NECA (a non-selective adenosine . A 3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics Pier Andrea Borea Editor A 3 Adenosine Receptors from Cell Biology to Pharmacology. “A 3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics an up to date, scientifically excellent, reference source, attractive to basic