TY - JOUR
T1 - Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function
AU - Moreno, José L.
AU - Muguruza, Carolina
AU - Umali, Adrienne
AU - Mortillo, Steven
AU - Holloway, Terrell
AU - Pilar-Cuéllar, Fuencisla
AU - Mocci, Giuseppe
AU - Seto, Jeremy
AU - Callado, Luis F.
AU - Neve, Rachael L.
AU - Milligan, Graeme
AU - Sealfon, Stuart C.
AU - López-Giménez, Juan F.
AU - Meana, J. Javier
AU - Benson, Deanna L.
AU - González-Maeso, Javier
PY - 2012/12/28
Y1 - 2012/12/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84871760600&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.413161
DO - 10.1074/jbc.M112.413161
M3 - Article
C2 - 23129762
AN - SCOPUS:84871760600
SN - 0021-9258
VL - 287
SP - 44301
EP - 44319
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 53
ER -