Dopamine D(1) receptor-induced gene transcription is modulated by DARPP-32.
The role of the dopamine- and cyclic AMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) in dopaminergic regulation of gene transcription in striatum and globus pallidus was examined. Mice with targeted disruption of the gene encoding DARPP-32, its homologue, inhibitor-1, or both, were used. Pharmacological characterization showed that mutant mice had normal basal levels of dopamine D(1) and D(2) receptors and adenosine A(2A) receptors. Basal expression levels of the striatonigral-specific neuropeptides substance P and prodynorphin and the immediate early genes c-fos and NGFI-A were also unaltered in mutant mice. A full D(1) receptor agonist, SKF 82958, up-regulated the expression of these neuropeptides and immediate early genes significantly more in wild-type mice than in mice lacking DARPP-32. Moreover, the additive stimulation of SKF 82958 and quinelorane, a D(2) receptor agonist, on c-fos mRNA in globus pallidus was significantly decreased in DARPP-32 and DARPP-32/I-1 knockout mice. No changes in dopamine receptor-induced gene expression were found in I-1 knockout mice. These results demonstrate an important involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and in pallidal neurons, which do not contain DARPP-32.
Svenningsson
P
P
Departments of. Physiology and Pharmacology. Neuroscience, Karolinska Institutet, Stockholm, Sweden. svennip@rockvax.rockefeller.edu
Fienberg
A A
AA
Allen
P B
PB
Moine
C L
CL
Lindskog
M
M
Fisone
G
G
Greengard
P
P
Fredholm
B B
BB
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D002421:Caudate Nucleus / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D005917:Globus Pallidus / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009714:Nucleus Accumbens / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D014158:Transcription, Genetic
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011804:Quinolines; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; C071262:SK&F 82958; C047726:quinelorane