Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum.
Copyright policy )Galpha(olf) levels are regulated by receptor usage and control dopamine and adenosine action in the striatum.
In the striatum, dopamine D(1) and adenosine A(2A) 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 Galpha(S) subunit or through the olfactory isoform, Galpha(olf), 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 D(1) receptor mRNA, contained high amounts of Galpha(olf) mRNA and undetectable levels of Galpha(s) mRNA. In contrast, the large cholinergic interneurons contained both Galpha(olf) and Galpha(s) transcripts. To assess the functional relationship between dopamine or adenosine receptors and G-proteins, we examined G-protein levels in the striatum of D(1) and A(2A) receptor knock-out mice. A selective increase in Galpha(olf) protein was observed in these animals, without change in mRNA levels. Conversely, Galpha(olf) levels were decreased in animals lacking a functional dopamine transporter. These results indicate that Galpha(olf) protein levels are regulated through D(1) and A(2A) receptor usage. To determine the functional consequences of changes in Galpha(olf) levels, we used heterozygous Galpha(olf) knock-out mice, which possess half of the normal Galpha(olf) 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 Galpha(olf) as a critical and regulated component of both dopamine and adenosine signaling.
- Neuro-SU France
- Inserm France
- French National Centre for Scientific Research France
- Université Libre de Bruxelles Belgium
Male, Adenosine, Dopamine, Dopamine D1 -- genetics, Motor Activity -- drug effects, Carrier Proteins -- metabolism, Dopamine D1 -- deficiency, Mice, Heterotrimeric GTP-Binding Proteins -- metabolism, Receptors, Dopamine D1 -- metabolism, Motor Activity -- genetics, Central Nervous System Stimulants -- pharmacology, In Situ Hybridization, Mice, Knockout, Neurons, Membrane Glycoproteins, Amphetamine -- pharmacology, Sciences bio-médicales et agricoles, Corpus Striatum -- metabolism, Heterotrimeric GTP-Binding Proteins, Organ Specificity, Caffeine -- pharmacology, Dopamine -- metabolism, Purinergic P1 -- deficiency, Receptor, Heterozygote, Purinergic P1 -- genetics, Purinergic P1 -- metabolism, Protein Isoforms -- genetics, Knockout, Nerve Tissue Proteins, Motor Activity, Protein Isoforms -- metabolism, Adenosine A2A, Heterotrimeric GTP-Binding Proteins -- genetics, Caffeine, Animals, Neurons -- metabolism, Dopamine Plasma Membrane Transport Proteins, Adenosine -- metabolism, Membrane Transport Proteins, Corpus Striatum, Rats, Messenger -- metabolism, Amphetamine, Neurons -- classification, Carrier Proteins -- genetics, RNA, Central Nervous System Stimulants, Sprague-Dawley, Carrier Proteins
Male, Adenosine, Dopamine, Dopamine D1 -- genetics, Motor Activity -- drug effects, Carrier Proteins -- metabolism, Dopamine D1 -- deficiency, Mice, Heterotrimeric GTP-Binding Proteins -- metabolism, Receptors, Dopamine D1 -- metabolism, Motor Activity -- genetics, Central Nervous System Stimulants -- pharmacology, In Situ Hybridization, Mice, Knockout, Neurons, Membrane Glycoproteins, Amphetamine -- pharmacology, Sciences bio-médicales et agricoles, Corpus Striatum -- metabolism, Heterotrimeric GTP-Binding Proteins, Organ Specificity, Caffeine -- pharmacology, Dopamine -- metabolism, Purinergic P1 -- deficiency, Receptor, Heterozygote, Purinergic P1 -- genetics, Purinergic P1 -- metabolism, Protein Isoforms -- genetics, Knockout, Nerve Tissue Proteins, Motor Activity, Protein Isoforms -- metabolism, Adenosine A2A, Heterotrimeric GTP-Binding Proteins -- genetics, Caffeine, Animals, Neurons -- metabolism, Dopamine Plasma Membrane Transport Proteins, Adenosine -- metabolism, Membrane Transport Proteins, Corpus Striatum, Rats, Messenger -- metabolism, Amphetamine, Neurons -- classification, Carrier Proteins -- genetics, RNA, Central Nervous System Stimulants, Sprague-Dawley, Carrier Proteins
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