Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor
The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D 1 receptor...
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| Published in: | Nature communications Vol. 9; no. 1; pp. 1 - 11 |
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| Main Authors: | , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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| Abstract | The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D
1
receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.
D1-like dopamine receptors are coupled to Golf proteins in the dorsal striatum but Gs in cortical and other areas. Here, the authors demonstrate selective agonism of Gs-coupled versus Golf-coupled D1 receptors. |
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| AbstractList | The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction. The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D 1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction. D1-like dopamine receptors are coupled to Golf proteins in the dorsal striatum but Gs in cortical and other areas. Here, the authors demonstrate selective agonism of Gs-coupled versus Golf-coupled D1 receptors. The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D 1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction. D1-like dopamine receptors are coupled to Golf proteins in the dorsal striatum but Gs in cortical and other areas. Here, the authors demonstrate selective agonism of Gs-coupled versus Golf-coupled D1 receptors. |
| ArticleNumber | 486 |
| Author | Yano, Hideaki Verma, Ravi Kumar Xu, Min Hoffman, Alexander F. Javitch, Jonathan A. Bonci, Antonello Shi, Lei Cai, Ning-Sheng Rea, William Ferré, Sergi |
| Author_xml | – sequence: 1 givenname: Hideaki surname: Yano fullname: Yano, Hideaki email: hideaki.yano@nih.gov organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 2 givenname: Ning-Sheng surname: Cai fullname: Cai, Ning-Sheng organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 3 givenname: Min surname: Xu fullname: Xu, Min organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 4 givenname: Ravi Kumar surname: Verma fullname: Verma, Ravi Kumar organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 5 givenname: William surname: Rea fullname: Rea, William organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 6 givenname: Alexander F. surname: Hoffman fullname: Hoffman, Alexander F. organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 7 givenname: Lei surname: Shi fullname: Shi, Lei organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 8 givenname: Jonathan A. surname: Javitch fullname: Javitch, Jonathan A. organization: Department of Psychiatry, College of Physicians & Surgeons, Columbia University, Division of Molecular Therapeutics, New York State Psychiatric Institute – sequence: 9 givenname: Antonello surname: Bonci fullname: Bonci, Antonello organization: National Institute on Drug Abuse, National Institutes of Health – sequence: 10 givenname: Sergi surname: Ferré fullname: Ferré, Sergi organization: National Institute on Drug Abuse, National Institutes of Health |
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| Snippet | The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is... D1-like dopamine receptors are coupled to Golf proteins in the dorsal striatum but Gs in cortical and other areas. Here, the authors demonstrate selective... |
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| SubjectTerms | 631/378/340 631/92/436/2387 64 64/110 9/10 9/74 Apomorphine Brain Cortex Dopamine Dopamine D1 receptors Drug screening Homology Humanities and Social Sciences Mental disorders multidisciplinary Neostriatum Proteins Science Science (multidisciplinary) Selectivity Signaling |
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| Title | Gs- versus Golf-dependent functional selectivity mediated by the dopamine D1 receptor |
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