Expression of the Adenosine A2A-A3 Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APPSw,Ind Alzheimer's Disease Model.

Alejandro Lillo,Gemma Navarro,Iu Raïch,Jaume Lillo,Catalina Pérez-Olives,Rafael Franco

doi:10.3390/biomedicines10020214

Abstract

Adenosine (Ado) receptors have been instrumental in the detection of heteromers and other higher-order receptor structures, mainly via interactions with other cell surface G-protein-coupled receptors. Apart from the first report of the A1 Ado receptor interacting with the A2A Ado receptor, there has been more recent data on the possibility that every Ado receptor type, A1, A2A, A2B, and A3, may interact with each other. The aim of this paper was to look for the expression and function of the A2A/A3 receptor heteromer (A2AA3Het) in neurons and microglia. In situ proximity ligation assays (PLA), performed in primary cells, showed that A2AA3Het expression was markedly higher in striatal than in cortical and hippocampal neurons, whereas it was similar in resting and activated microglia. Signaling assays demonstrated that the effect of the A2AR agonist, PSB 777, was reduced in the presence of the A3R agonist, 2-Cl-IB-MECA, whereas the effect of the A3R agonist was potentiated by the A2AR antagonist, SCH 58261. Interestingly, the expression of the heteromer was markedly enhanced in microglia from the APPSw,Ind model of Alzheimer’s disease. The functionality of the heteromer in primary microglia from APPSw,Ind mice was more similar to that found in resting microglia from control mice.

Highlights

Adenosine (Ado) is a nucleoside that participates in the metabolism of nucleic acids, of enzyme cofactors/substrates, and of energy-related relevant molecules, such as ATP
One of the functions of the nucleoside is to be a warning for excess energy expenditure or for hypoxia; in such conditions, ATP is converted to Ado, whose presence activates Ado receptors on the cell surface
There are four Ado receptors whose affinity for Ado varies and that belong to the rhodopsin-like class A G protein-coupled receptors (GPCRs): A1, A2A, A2B, and A3

Summary

Introduction

Adenosine (Ado) is a nucleoside that participates in the metabolism of nucleic acids, of enzyme cofactors/substrates (nicotinamide adenine nucleotides, flavin-adenine dinucleotides etc.), and of energy-related relevant molecules, such as ATP. One of the functions of the nucleoside is to be a warning for excess energy expenditure or for hypoxia; in such conditions, ATP is converted to Ado, whose presence activates Ado receptors on the cell surface. There are four Ado receptors whose affinity for Ado varies and that belong to the rhodopsin-like class A G protein-coupled receptors (GPCRs): A1 , A2A , A2B , and A3. Activation of the A2A R or the A2B R leads to increases of [cAMP] and Biomedicines 2022, 10, 214. Biomedicines 2022, 10, 214 engagement of the protein kinase A-mediated signaling pathway whereas activation of. Research on Ado receptors has been instrumental to identify a variety of heteromers starting with those established in the striatum with dopamine receptors [2,3]

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