Adenosine A 2A receptors and A 2A receptor heteromers as key players in striatal function

Abstract

A very significant density of adenosine A 2A receptors (A 2ARs) is present in the striatum, where they are preferentially localized postsynaptically in striatopallidal medium spiny neurons (MSNs). In this localization A 2ARs establish reciprocal antagonistic interactions with dopamine D 2 receptors (D 2Rs). In one type of interaction, A 2AR and D 2R are forming heteromers and, by means of an allosteric interaction, A 2AR counteracts D 2R-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striatopallidal neuron. This interaction is probably mostly responsible for the locomotor depressant and activating effects of A 2AR agonist and antagonists, respectively. The second type of interaction involves A 2AR and D 2R that do not form heteromers and takes place at the level of adenylyl cyclase (AC). Due to a strong tonic effect of endogenous dopamine on striatal D 2R, this interaction keeps A 2AR from signaling through AC. However, under conditions of dopamine depletion or with blockade of D 2R, A 2AR-mediated AC activation is unleashed with an increased gene expression and activity of the striatopallidal neuron and with a consequent motor depression.This interaction is probably the main mechanism responsible for the locomotor depression induced by D 2R antagonists. Finally, striatal A 2ARs are also localized presynaptically, in cortico-striatal glutamatergic terminals that contact the striato-nigral MSN. These presynaptic A 2ARs heteromerize with A 1 receptors (A 1Rs) and their activation facilitates glutamate release. These three different types of A 2ARs can be pharmacologically dissected by their ability to bind ligands with different affinity and can therefore provide selective targets for drug development in different basal ganglia disorders. © 2011 Ferré, Quiroz, Orru, Guitart, Navarro, Cortés, Casadó, Canela, Lluis and Franc.