Functional and Neuroprotective Role of Striatal Adenosine A_2AReceptor Heterotetramers

Abstract

In the striatum, adenosine A 2A receptors (A 2A R) are mainly expressed within the soma and dendrites of the striatopallidal neuron. A predominant proportion of these striatal postsynaptic A 2A R form part of the macromolecular complexes that include A 2A R-dopamine D 2 receptor (D 2 R) heteromers, G olf and G i/o proteins, and the effector adenylyl cyclase (AC), subtype AC5. The A 2A R-D 2 R heteromers have a tetrameric structure, constituted by A 2A R and D 2 R homomers. By means of reciprocal antagonistic allosteric interactions and antagonistic interactions at the effector level between adenosine and dopamine, the A 2A R-D 2 R heterotetramer-AC5 complex acts an integrative molecular device, which determines a switch between the adenosine-facilitated activation and the dopamine-facilitated inhibition of the striatopallidal neuron. Striatal adenosine also plays an important presynaptic modulatory role, driving the function of corticostriatal terminals. This control is mediated by adenosine A 1 receptors (A 1 R) and A 2A R, which establish intermolecular interactions forming A 1 R-A 2A R heterotetramers. Here, we review the functional role of both presynaptic and postsynaptic striatal A 2A R heterotetramers as well as their possible neuroprotective role. We hypothesize that alterations in the homomer/heteromer stoichiometry (i.e., increase or decrease in the proportion of A 2A R forming homomers or heteromers) are pathogenetically involved in neurological disorders, specifically in Parkinson's disease and restless legs syndrome.

Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

“…A 2A R/D 2 R heteromers are now considered to be receptor heterotetramers, consisting of an A 2A R homodimer and a D 2 R homodimer, each coupled to its own G-protein (Gs and Gi, respectively). Adenylate cyclase subtype AC5 also forms part of this multi-protein complex [ 41 , 120 , 121 , 122 , 123 , 124 , 125 ]. The heterotetramer model can explain the apparently paradoxical effects of A 2A R agonists and antagonists on D 2 R ligand binding in CHO cells that were described in Section 2.3 of this review.…”

“…Synthetic peptides that interact with the receptor domains involved in heteromer formation affect the electrostatic interactions between the protomers and alter the response of cells to certain drugs ( Section 5 ). In addition, within A 2A R/D 2 R heterotetramers, various receptor–receptor interactions are possible [ 125 ]:…”

Guanosine Mechanisms of Action: Toward Molecular Targets

“…This oligomerization induces changes in biochemical properties of GPCRs. It is well established that adenosine receptors can form oligomers among themselves and with receptors for other neurotransmitters, such as dopamine receptors ( Ginés et al, 2000 ; Fuxe et al, 2005 ; Ciruela et al, 2006 ; Navarro, et al, 2018 ; Borroto-Escuela et al, 2018 ; Ferré and Ciruela 2019 ; Cortés et al, 2019 ). It is known that A 1 and A 2A receptors form functional oligomers with each other and that the A 1 R-A 2A R heteromer plays an important role in modulating the control of cortico-striatal function ( Ciruela et al, 2006 ).…”

Crosstalk Between ATP-P2X7 and Adenosine A2A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress

“…The detailed mechanisms of this P 2X7 R-A 2A R interactions also remain to be unraveled and they can involve different possibilities: one possibility is the formation of heteromers, which has been documented for P 2X7 R (Antonio et al, 2011 ) and for A 2A R (reviewed in Ferré and Ciruela, 2019 ) and between different P 2 R and P 1 R (Namba et al, 2010 ); another possibility is the use of transducing systems of each receptor to control the other receptor function, as has been shown for P 2X7 R controlling metabotropic receptors (reviewed in Miras-Portugal et al, 2019 ), A 2A R controlling ionotropic receptors (e.g., Garção et al, 2013 ; Temido-Ferreira et al, 2020 ) and between different P 2 R and P 1 R (George et al, 2016 ); a third possibility is a key role of ecto-nucleotidases metabolizing ATP into adenosine in a rapid (Dunwiddie et al, 1997 ; Cunha et al, 1998 ) and highly controlled manner (James and Richardson, 1993 ; Cunha, 2001 ) to format the balanced activation of both receptors (Kukley et al, 2004 ; Liston et al, 2020 ). After this first step establishing an interaction between A 2A R and P 2X7 R, future work will be required to detail the mechanistic basis of this A 2A R-P 2X7 R interaction.…”