Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors.
In the striatum, stimulation of dopamine D2 receptors results in attenuation of glutamate responses. This effect is exerted in large part via negative regulation of AMPA glutamate receptors. Phosphorylation of the GluR1 subunit of the AMPA receptor has been proposed to play a critical role in the modulation of glutamate transmission, in striatal medium spiny neurons. Here, we have examined the effects of blockade of dopamine D2-like receptors on the phosphorylation of GluR1 at the cAMP-dependent protein kinase (PKA) site, Ser845, and at the protein kinase C and calcium/calmodulin-dependent protein kinase II site, Ser831. Administration of haloperidol, an antipsychotic drug with dopamine D2 receptor antagonistic properties, increases the phosphorylation of GluR1 at Ser845, without affecting phosphorylation at Ser831. The same effect is observed using eticlopride, a selective dopamine D2 receptor antagonist. In contrast, administration of the dopamine D2-like agonist, quinpirole, decreases GluR1 phosphorylation at Ser845. The increase in Ser845 phosphorylation produced by haloperidol is abolished in dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) knockout mice, or in mice in which the PKA phosphorylation site on DARPP-32 (i.e. Thr34) has been mutated (Thr34-->Ala mutant mice), and requires tonic activation of adenosine A2A receptors. These results demonstrate that dopamine D2 antagonists increase GluR1 phosphorylation at Ser845 by removing the inhibitory tone exerted by dopamine D2 receptors on the PKA/DARPP-32 cascade.
Håkansson
Kerstin
K
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Galdi
Stacey
S
Hendrick
Joseph
J
Snyder
Gretchen
G
Greengard
Paul
P
Fisone
Gilberto
G
D058917:Adenosine A2 Receptor Antagonists; D000595:Amino Acid Sequence; D000818:Animals; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D018091:Receptors, AMPA / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology*; D012694:Serine; D013912:Threonine
D058917:Adenosine A2 Receptor Antagonists; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D006220:Haloperidol; D011687:Purines; D019257:Quinpirole; D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2; D012694:Serine; D013912:Threonine; C497929:Ppp1r1b protein, mouse; C111599:istradefylline