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 M112.413161
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
Mice RBRC01351