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Potentiation of cannabinoid signaling in microglia by adenosine A 2A receptor antagonists
Author(s) -
Franco Rafael,
ReyesResina Irene,
Aguinaga David,
Lillo Alejandro,
Jiménez Jasmina,
Raïch Iu,
BorrotoEscuela Dasiel O.,
FerreiroVera Carlos,
Canela Enric I.,
Sánchez de Medina Verónica,
SerBadia Anna,
Fuxe Kjell,
Saura Carlos A.,
Navarro Gemma
Publication year - 2019
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23694
Subject(s) - neuroprotection , microglia , g protein coupled receptor , neuroscience , receptor , biology , cannabinoid , adenosine a2a receptor , neurodegeneration , long term potentiation , adenosine receptor , pharmacology , agonist , medicine , biochemistry , immunology , inflammation , disease
Neuroprotective M2‐skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein‐coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A 2A (A 2A R) and cannabinoid CB 2 (CB 2 R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB 2 R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A 2A R antagonists reduce amyloid burden and improve cognitive performance and memory in AD animal models. We here show a close interrelationship between these two receptors in microglia; they are able to physically interact and affect the signaling of each other, likely due to conformational changes within the A 2A ‐CB 2 receptor heteromer (A 2A ‐CB 2 Het). Particularly relevant is the upregulation of A 2A ‐CB 2 Het expression in samples from the APP Sw , Ind AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A 2A receptors results in increased CB 2 R‐mediated signaling. This heteromer‐specific feature suggests that A 2A R antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.