title: Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia.
abstract: 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 Gi/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.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Miranda-Azpiazu
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Pharmacology, University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain.
authors.forename: Aintzane
authors.initials: A
authors.lastname: García-Bea
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Younkin
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Cui
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kozlenkov
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Ben-Ezra
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Georgios
authors.initials: G
authors.lastname: Voloudakis
authors.affiliation: Department of Anesthesiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Fakira
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Lia
authors.initials: L
authors.lastname: Baki
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
authors.affiliation: Department of Anesthesiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: José A
authors.initials: JA
authors.lastname: Morón
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.affiliation: Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC-CSIC-UC), E-39011 Santander, Cantabria, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: López-Giménez
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.affiliation: Department of Pharmacology, University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), University of the Basque Country UPV/EHU, E-48940 Leioa, Bizkaia, Spain. BioCruces Health Research Institute, E-48903 Barakaldo, Bizkaia, Spain. javier.meana@ehu.eus jgmaeso@vcu.edu.
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. javier.meana@ehu.eus jgmaeso@vcu.edu.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D055503:Protein Multimerization; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11