Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia

José L. Moreno, Patricia Miranda-Azpiazu, Aintzane García-Bea, Jason Younkin, Meng Cui, Alexey Kozlenkov, Ariel Ben-Ezra, Georgios Voloudakis, Amanda K. Fakira, Lia Baki, Yongchao Ge, Anastasios Georgakopoulos, José A. Morón, Graeme Milligan, Juan F. López-Giménez, Nikolaos K. Robakis, Diomedes E. Logothetis, J. Javier Meana, Javier González-Maeso

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptor-GPCRs that are involved in signaling alterations associated with psychosis-assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2-5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to G i/o proteins, and we determined the relative location of the Gi/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of Gq/11, but not Gi/o, was reduced in the frontal cortex of 5-HT2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry.

Original languageEnglish
JournalScience Signaling
Issue number410
StatePublished - 12 Jan 2016


Dive into the research topics of 'Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia'. Together they form a unique fingerprint.

Cite this