Direct involvement of σ-1 receptors in the dopamine D 1 receptor-mediated effects of cocaine
| Autor: | Rafael Franco, Enric I. Canela, Sergi Ferré, Kjell Fuxe, Gemma Navarro, Carmen Lluis, Josefa Mallol, Daniel Marcellino, Jordi Ortiz, Antoni Cortés, Vicent Casadó, Peter J. McCormick, M.S. Aymerich, Estefanía Moreno |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
MAP Kinase Signaling System D1-like receptor CHO Cells Pharmacology Transfection Cell Line Cocaine-Related Disorders Mice Cricetulus Dopamine receptor D1 Cocaine Dopamine Cricetinae medicine Animals Humans Receptors sigma Protein Structure Quaternary Receptor Dopamine transporter Mice Knockout Multidisciplinary biology Chemistry Receptors Dopamine D1 Dopaminergic Brain Biological Sciences Recombinant Proteins D2-like receptor Dopamine receptor biology.protein Dimerization medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:18676-18681 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1008911107 |
| Popis: | It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D 1 receptors (D 1 Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, D 1 R and σ 1 R were found to heteromerize in transfected cells, where cocaine robustly potentiated D 1 R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D 1 R stimulation in a dopamine transporter-independent and σ 1 R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ 1 R KO mice, providing evidence for the existence of σ 1 R-D 1 R heteromers in the brain. Therefore, these results provide a molecular explanation for which D 1 R plays a more significant role in the behavioral effects of cocaine, through σ 1 R-D 1 R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|