Identification of Three Residues Essential for 5-Hydroxytryptamine 2A-Metabotropic Glutamate 2 (5-HT2A·mGlu2) Receptor Heteromerization and Its Psychoactive Behavioral Function
| Autor: | Rachael L. Neve, Giuseppe Mocci, Graeme Milligan, Juan F. López-Giménez, Adrienne Umali, Carolina Muguruza, Terrell Holloway, José L. Moreno, Jeremy Seto, Luis F. Callado, Deanna L. Benson, Steven Mortillo, Javier González-Maeso, J. Javier Meana, Stuart C. Sealfon, Fuencisla Pilar-Cuéllar |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Receptor complex Mice 129 Strain Amino Acid Motifs Molecular Sequence Data Heteromer Biology Receptors Metabotropic Glutamate Biochemistry Mice Young Adult Neurobiology Enzyme-linked receptor Animals Humans Receptor Serotonin 5-HT2A 5-HT5A receptor Amino Acid Sequence Molecular Biology Mice Knockout Behavior Metabotropic glutamate receptor 5 Metabotropic glutamate receptor 4 Cell Biology Middle Aged Cell biology Amino Acid Substitution Case-Control Studies Schizophrenia Metabotropic glutamate receptor 1 Female Schizophrenic Psychology Metabotropic glutamate receptor 2 Dimerization Sequence Alignment Protein Binding |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0021-9258 2009-0846 |
| DOI: | 10.1074/jbc.m112.413161 |
| Popis: | El pdf del artículo es la versión post-print.-- et al. Serotonin and glutamate G protein-coupled receptor (GPCR) neurotransmission affects cognition and perception in humans and rodents. GPCRs are capable of forming heteromeric complexes that differentially alter cell signaling, but the role of this structural arrangement in modulating behavior remains unknown. Here, we identified three residues located at the intracellular end of transmembrane domain four that are necessary for the metabotropic glutamate 2 (mGlu2) receptor to be assembled as a GPCR heteromer with the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor in the mouse frontal cortex. Substitution of these residues (Ala-6774.40, Ala-6814.44, and Ala-6854.48) leads to absence of 5-HT2A·mGlu2 receptor complex formation, an effect that is associated with a decrease in their heteromeric ligand binding interaction. Disruption of heteromeric expression with mGlu2 attenuates the psychosis-like effects induced in mice by hallucinogenic 5-HT2A agonists. Furthermore, the ligand binding interaction between the components of the 5-HT2A·mGlu2 receptor heterocomplex is up-regulated in the frontal cortex of schizophrenic subjects as compared with controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer. This work was supported, in whole or in part, by National Institutes of Health Grants R01 MH084894 (to J.G.M.), R01 NS37731 (to D.L.B.), and P01 DA12923 (to S.C.S.). This work was also supported by Dainippon Sumi-tomo Pharma (to J.G.M.), National Alliance for Research on Schizophrenia and Depression (to J.G.M.), The Mortimer D. Sackler Foundation (to J.G.M.), Ministerio de Ciencia e Innovación Grant SAF2009-084609 (to J.J.M.), Basque Government Grant IT-199-07 (to J.J. M.), Consejo Superior de Investigaciones Científicas Grants PA1003176 and 200980I110 (to J.F.L.-G.), and Medical Research Council United Kingdom Grant G0900050 (to G.M.). Recipient of a predoctoral fellowship from University of the Basque Country, Spain. Recipient of a postdoctoral fellowship from Fundacion Alicia Koplowitz, Spain. Recipient of a predoctoral fellowship from Consejo Superior de Investigaciones Científicas, Spain. |
| Databáze: | OpenAIRE |
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