Search

Adenosine modulates neurotransmission through inhibitory adenosine A

Adenosine plays a very significant role in modulating striatal glutamatergic and dopaminergic neurotransmission. In the present essay we first review the extensive evidence that indicates this modulation is mediated by adenosine A1 and A2A receptors (A1Rs and A2ARs) differentially expressed by the components of the striatal microcircuit that include cortico-striatal glutamatergic and mesencephalic dopaminergic terminals, and the cholinergic interneuron. This microcircuit mediates the ability of striatal glutamate release to locally promote dopamine release through the intermediate activation of cholinergic interneurons. A1Rs and A2ARs are colocalized in the cortico-striatal glutamatergic terminals, where they form A1R-A2AR and A2AR-cannabinoid CB1 receptor (CB1R) heteromers. We then evaluate recent findings on the unique properties of A1R-A2AR and A2AR-CB1R heteromers, which depend on their different quaternary tetrameric structure. These properties involve different allosteric mechanisms in the two receptor heteromers that provide fine-tune modulation of adenosine and endocannabinoid-mediated striatal glutamate release. Finally, we evaluate the evidence supporting the use of different heteromers containing striatal adenosine receptors as targets for drug development for neuropsychiatric disorders, such as Parkinson's disease and restless legs syndrome, based on the ability or inability of the A2AR to demonstrate constitutive activity in the different heteromers, and the ability of some A2AR ligands to act preferentially as neutral antagonists or inverse agonists, or to have preferential affinity for a specific A2AR heteromer.

Adenosine modulates neurotransmission through inhibitory adenosine A1 receptors (A1Rs) and stimulatory A2A receptors (A2ARs). These G protein-coupled receptors are involved in motor function and related to neurodegenerative diseases such as Parkinson's disease (PD). An autosomal-recessive mutation (G2797.44S) within the transmembrane helix (TM) 7 of A1R (A1RG279S) has been associated with the development of early onset PD (EOPD). Here, we aimed at investigating the impact of this mutation on the structure and function of the A1R and the A1R-A2AR heteromer. Our results revealed that the G2797.44S mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins (Gαi, Gαq, Gα12/13, Gαs, β-arrestin2 and GRK2) in transfected HEK-293 T cells. However, A1RG279S weakened the ability of A1R to heteromerize with A2AR, as shown in a NanoBiT assay, which led to the disappearance of the heteromerization-dependent negative allosteric modulation that A1R imposes on the constitutive activity and agonist-induced activation of the A2AR. Molecular dynamic simulations allowed to propose an indirect mechanism by which the G2797.44S mutation in TM 7 of A1R weakens the TM 5/6 interface of the A1R-A2AR heteromer. Therefore, it is demonstrated that a PD linked ADORA1 mutation is associated with dysfunction of adenosine receptor heteromerization. We postulate that a hyperglutamatergic state secondary to increased constitutive activity and sensitivity to adenosine of A2AR not forming heteromers with A1R could represent a main pathogenetic mechanism of the EOPD associated with the G2797.44S ADORA1 mutation.