Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function.
The physiological meaning of the coexpression of adenosine A2A receptors and group I metabotropic glutamate receptors in gamma- aminobutyric acid (GABA)ergic striatal neurons is intriguing. Here we provide in vitro and in vivo evidence for a synergism between adenosine and glutamate based on subtype 5 metabotropic glutamate (mGluR5) and adenosine A2A (A2AR) receptor/receptor interactions. Colocalization of A2AR and mGluR5 at the membrane level was demonstrated in nonpermeabilized human embryonic kidney (HEK)-293 cells transiently cotransfected with both receptors by confocal laser microscopy. Complexes containing A2AR and mGluR5 were demonstrated by Western blotting of immunoprecipitates of either Flag-A2AR or hemagglutinin-mGluR5 in membrane preparations from cotransfected HEK-293 cells and of native A2AR and mGluR5 in rat striatal membrane preparations. In cotransfected HEK-293 cells a synergistic effect on extracellular signal-regulated kinase 1/2 phosphorylation and c-fos expression was demonstrated upon A2AR/mGluR5 costimulation. No synergistic effect was observed at the second messenger level (cAMP accumulation and intracellular calcium mobilization). Accordingly, a synergistic effect on c-fos expression in striatal sections and on counteracting phencyclidine-induced motor activation was also demonstrated after the central coadministration of A2AR and mGluR5 agonists to rats with intact dopaminergic innervation. The results suggest that a functional mGluR5/A2AR interaction is required to overcome the well-known strong tonic inhibitory effect of dopamine on striatal adenosine A2AR function.
Ferré
Sergi
S
Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, Baltimore, MD 21224, U SA. sferre@intra.nida.nih.gov
Karcz-Kubicha
Marzena
M
Hope
Bruce T
BT
Popoli
Patrizia
P
Burgueño
Javier
J
Gutiérrez
M Angeles
MA
Casadó
Vicent
V
Fuxe
Kjell
K
Goldberg
Steven R
SR
Lluis
Carme
C
Franco
Rafael
R
Ciruela
Francisco
F
D000818:Animals; D002460:Cell Line; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010622:Phencyclidine / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism*
C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D016760:Proto-Oncogene Proteins c-fos; D043705:Receptor, Adenosine A2A; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018047:Receptors, Purinergic P1; D010622:Phencyclidine