Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function

José L. Moreno, Carolina Muguruza, Adrienne Umali, Steven Mortillo, Terrell Holloway, Fuencisla Pilar-Cuéllar, Giuseppe Mocci, Jeremy Seto, Luis F. Callado, Rachael L. Neve, Graeme Milligan, Stuart C. Sealfon, Juan F. López-Giménez, J. Javier Meana, Deanna L. Benson, Javier González-Maeso

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

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-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.

Original languageEnglish
Pages (from-to)44301-44319
Number of pages19
JournalJournal of Biological Chemistry
Volume287
Issue number53
DOIs
StatePublished - 28 Dec 2012

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