title: Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function.
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.
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.forename: Carolina
authors.initials: C
authors.lastname: Muguruza
authors.forename: Adrienne
authors.initials: A
authors.lastname: Umali
authors.forename: Steven
authors.initials: S
authors.lastname: Mortillo
authors.forename: Terrell
authors.initials: T
authors.lastname: Holloway
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Pilar-Cuéllar
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mocci
authors.forename: Jeremy
authors.initials: J
authors.lastname: Seto
authors.forename: Luis F
authors.initials: LF
authors.lastname: Callado
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Graeme
authors.initials: G
authors.lastname: Milligan
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Sealfon
authors.forename: Juan F
authors.initials: JF
authors.lastname: López-Giménez
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Meana
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Benson
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
mesh_terms: D000328:Adult; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001519:Behavior; D016022:Case-Control Studies; D019281:Dimerization; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D011485:Protein Binding; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D012565:Schizophrenic Psychology; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2