Role of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2A receptor signaling in the neostriatum.
Adenosine is known to modulate the function of neostriatal neurons. Adenosine acting on A(2A) receptors increases the phosphorylation of dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) at Thr34 (the cAMP-dependent protein kinase [PKA] site) in striatopallidal neurons, and opposes dopamine D2 receptor signaling. In contrast, the role of adenosine A(1) receptors in the regulation of dopamine/DARPP-32 signaling is not clearly understood. Here, we investigated the effect of adenosine A(1) receptors on D(1), D(2) and A(2A) receptor signaling using mouse neostriatal slices. An A(1) receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (100 nM), caused a transient increase, followed by a transient decrease, in DARPP-32 Thr34 phosphorylation. Our data support the following model for the actions of the A(1) receptor agonist. The A(1) receptor-induced early increase in Thr34 phosphorylation was mediated by presynaptic inhibition of dopamine release, and the subsequent removal of tonic inhibition by D(2) receptors of A(2A) receptor/G(olf)/cAMP/PKA signaling. The A(1) receptor-induced late decrease in Thr34 phosphorylation was mediated by a postsynaptic G(i) mechanism, resulting in inhibition of D(1) and A(2A) receptor-coupled G(olf)/cAMP/PKA signaling in direct and indirect pathway neurons, respectively. In conclusion, A(1) receptors play a major modulatory role in dopamine and adenosine receptor signaling.
Yabuuchi
K
K
Oita University Faculty of Medicine, Yufu, Oita 879-5593, Japan.
Kuroiwa
M
M
Shuto
T
T
Sotogaku
N
N
Snyder
G L
GL
Higashi
H
H
Tanaka
M
M
Greengard
P
P
Nishi
A
A
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000166:cytology / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013912:Threonine / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D001552:Benzazepines; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D010627:Phenethylamines; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D014227:Triazines; D014230:Triazoles; D014970:Xanthines; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D013912:Threonine; C058394:2-chloro-N(6)cyclopentyladenosine; D020891:Raclopride; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine