Full-length reviewCentral adenosine A2A receptors: an overview
Introduction
The purine nucleoside adenosine and its various receptor subtypes play multiple functions in the modulation of different central nervous system activities 31, 49, 54, 64, 133, 134, 150, 154. Adenosine exerts its physiological actions through activation of a number of specific cell surface receptors. Four adenosine receptors (A1, A2A, A2B, A3), belonging to the family of G protein-coupled receptors, are known so far and have been cloned and pharmacologically characterized. The A1 receptor (326 amino acids) was cloned from various species (human, rat, chick, dog, bovine, guinea-pig) with 90–95% sequence identity among the mammalian species. The A2B receptor (332 amino acids) was cloned from human and mouse 115, 142with ∼45% homology of human A2B with human A1 and A2A receptors [142]. The A3 receptor (337 amino acids) was cloned from human, rat, dog, rabbit and sheep 68, 108, 125, 161. Human A3 receptor shows 72% and 85% identity with rat and sheep A3 receptor, respectively [164]. The A2A receptor will be discussed in detail below.
Endogenous adenosine was first described to exert a powerful depressant effect on neuronal activities [41]. This inhibitory tonus results from activation of A1 receptors. However, at low concentrations, excitatory actions of adenosine have also been demonstrated [130]. Over the last few years, the development of agonists and antagonists more selective for the various adenosine receptor subtypes (see Table 1) has allowed to attribute these adenosine-induced excitatory effects to activation of A2A receptors. These receptors play an important role in the modulation of the release of several neurotransmitters and neuromodulators such as acetylcholine, dopamine, glutamate, GABA or various neuropeptides 103, 153. The aim of this article is to review the properties of brain adenosine A2A receptors and to examine their potential functions in physiological as well as pathological conditions.
Section snippets
Molecular characteristics
The A2A receptor gene has been cloned from various mammalian species (human, rat, mouse, dog and guinea pig). The human cDNA encoding 412 amino acids was isolated from a hippocampal library [57], the rat receptor from a rat kidney library [189], the mouse receptor from a brain and a bone marrow-derived mast cell library [115]and finally a full-length A2A receptor cDNA encoding 409 amino acids was cloned from guinea pig brain [116]. The overall homology of the A2A receptors among these species
A2A receptor-mediated behavioral responses
As outlined in the next sections and summarized in Table 2, the A2A receptor is thought to play a role in a number of physiological responses and pathological conditions.
Potential implication of central A2A receptors in human disorders
As outlined in the previous sections many animal studies describe the various roles of the adenosine system in brain function. In particular, the A2A receptor has been potentially involved in a variety of pathological events in animals that could be assumed to translate into normal aging or disorders such as Alzheimer's disease, epilepsy or ischemia in humans. Due to a lack of selective brain-penetrating nontoxic A2A receptor ligands, little clinical information is available to evaluate the
Concluding remarks
Due to their particular distribution in the brain and their functional properties, A2A receptors constitute an attractive opportunity for developing innovative compounds for the treatment of specific neurodegenerative and psychiatric disorders (see Table 2). However, it should not be forgotten that A2A receptors are also present in the periphery. This may relate to potential side effects associated with acute or chronic treatment with A2A receptor ligands which may act both at the peripheral
Acknowledgements
We are grateful to Drs. Borroni, Higgins and Kilpatrick for critical reading of the manuscript.
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