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The Journal of Neuroscience, June 15, 2001, 21(12):4390-4399
G olf Levels Are Regulated by Receptor Usage and
Control Dopamine and Adenosine Action in the Striatum
Denis
Hervé1,
Catherine
Le Moine2,
Jean-Christophe
Corvol1,
Leonardo
Belluscio3,
Catherine
Ledent4,
Allen A.
Fienberg5,
Mohamed
Jaber6,
Jeanne-Marie
Studler1, and
Jean-Antoine
Girault1
1 Institut National de la Santé et de la
Recherche Médicale (INSERM) U536, Institut du Fer à Moulin,
75005 Paris, France, 2 Centre National de la Recherche
Scientifique Unité Mixte 5541, Laboratoire
d'Histologie-Embryologie, Université Victor Segalen Bordeaux 2, 33076 Bordeaux cedex, France, 3 Department of Neurobiology,
Duke University Medical Center, Durham, North Carolina 27710, 4 Institut de Recherche Interdisciplinaire en Biologie
Humaine et Nucléaire, Université Libre de Bruxelles,
Campus Erasme, B-1070 Bruxelles, Belgium, 5 Laboratory of
Molecular and Cellular Neuroscience, The Rockefeller University, New
York, New York 10021, and 6 INSERM U259, Institut
François Magendie, Université Bordeaux II, 33077 Bordeaux
cedex, France
In the striatum, dopamine D1 and adenosine
A2A receptors stimulate the production of cAMP, which is
involved in neuromodulation and long-lasting changes in gene expression
and synaptic function. Positive coupling of receptors to adenylyl
cyclase can be mediated through the ubiquitous GTP-binding protein
G S subunit or through the olfactory isoform,
Golf, which predominates in the striatum. In this
study, using double in situ hybridization, we show that virtually all striatal efferent neurons, identified by the expression of preproenkephalin A, substance P, or D1 receptor mRNA,
contained high amounts of Golf mRNA and undetectable
levels of Gs mRNA. In contrast, the large cholinergic
interneurons contained both Golf and Gs
transcripts. To assess the functional relationship between dopamine or
adenosine receptors and G-proteins, we examined G-protein levels in the
striatum of D1 and A2A receptor knock-out mice.
A selective increase in Golf protein was observed in
these animals, without change in mRNA levels. Conversely,
Golf levels were decreased in animals lacking a
functional dopamine transporter. These results indicate that
Golf protein levels are regulated through D1
and A2A receptor usage. To determine the functional consequences of changes in Golf levels, we used
heterozygous Golf knock-out mice, which possess half of
the normal Golf levels. In these animals, the locomotor
effects of amphetamine and caffeine, two psychostimulant drugs that
affect dopamine and adenosine signaling, respectively, were markedly
reduced. Together, these results identify Golf as a
critical and regulated component of both dopamine and adenosine signaling.
Key words:
Golf; Gs; G-protein; D1 receptor; A2A receptor; knock-out mice; striatum; dopamine; adenosine; dopamine transporter; homologous recombination
Copyright © 2001 Society for Neuroscience 0270-6474/01/21124390-10$05.00/0
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