Reference - Detail
| RRC ID | 19388 |
|---|---|
| Author | Moreno JL, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuéllar F, Mocci G, Seto J, Callado LF, Neve RL, Milligan G, Sealfon SC, López-Giménez JF, Meana JJ, Benson DL, González-Maeso J. |
| Title | Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function. |
| Journal | J Biol Chem |
| Abstract |
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-HT(2A)) receptor in the mouse frontal cortex. Substitution of these residues (Ala-677(4.40), Ala-681(4.44), and Ala-685(4.48)) leads to absence of 5-HT(2A)·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-HT(2A) agonists. Furthermore, the ligand binding interaction between the components of the 5-HT(2A)·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. |
| Volume | 287(53) |
| Pages | 44301-19 |
| Published | 2012-12-28 |
| DOI | 10.1074/jbc.M112.413161 |
| PII | S0021-9258(20)41667-9 |
| PMID | 23129762 |
| PMC | PMC3531745 |
| MeSH | Adult Amino Acid Motifs Amino Acid Sequence Amino Acid Substitution Animals Behavior Case-Control Studies Dimerization Female Humans Male Mice Mice, 129 Strain Mice, Knockout Middle Aged Molecular Sequence Data Protein Binding Receptor, Serotonin, 5-HT2A / genetics Receptor, Serotonin, 5-HT2A / metabolism* Receptors, Metabotropic Glutamate / chemistry* Receptors, Metabotropic Glutamate / genetics Receptors, Metabotropic Glutamate / metabolism* Schizophrenia / genetics Schizophrenia / metabolism* Schizophrenic Psychology* Sequence Alignment Young Adult |
| IF | 4.238 |
| Times Cited | 69 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
|
| The most frequently cited source | |
| Total number of mentions | 15 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Mice | RBRC01351 |