| 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
|
| Resource |
| Mice |
RBRC01351 |
