Central adenosine A_2A receptors: an overview

Abstract

Recent advances in molecular biology, biochemistry, cell biology and behavioral pharmacology together with the development of more selective ligands to the various adenosine receptors have increased our understanding of the functioning of central adenosine A_2A receptors. The A_2A receptor is one of four adenosine receptors found in the brain. Its expression is highest in striatum, nucleus accumbens and olfactory tubercles, although it also occurs in neurons and microglia in most other brain regions. The receptor has seven transmembrane domains and couples via Gs to adenyl cyclase stimulation. Antagonistic interactions between A_2A receptors and dopamine D₂ receptors have been described, as stimulation of the A_2A receptor leads to a reduction in the affinity of D₂ receptors for D₂ receptor agonists. The A_2A receptor is thought to play a role in a number of physiological responses and pathological conditions. Indeed, A_2A receptor antagonists may be useful for the treatment of acute and chronic neurodegenerative disorders such as cerebral ischemia or Parkinson's disease. A_2A receptor agonists may treat certain types of seizures or sleep disorders. This review discusses the characteristics, distribution, pharmacochemical properties and regulation of central A_2A receptors, as well as A_2A receptor-mediated behavioural responses and their potential role in various neuropsychiatric disorders.

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, A_2A, A_2B, 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 A_2B receptor (332 amino acids) was cloned from human and mouse 115, 142with ∼45% homology of human A_2B with human A₁ and A_2A 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 A_2A 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 A_2A 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 A_2A receptors and to examine their potential functions in physiological as well as pathological conditions.