TY - JOUR
T1 - Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia
AU - Moreno, José L.
AU - Miranda-Azpiazu, Patricia
AU - García-Bea, Aintzane
AU - Younkin, Jason
AU - Cui, Meng
AU - Kozlenkov, Alexey
AU - Ben-Ezra, Ariel
AU - Voloudakis, Georgios
AU - Fakira, Amanda K.
AU - Baki, Lia
AU - Ge, Yongchao
AU - Georgakopoulos, Anastasios
AU - Morón, José A.
AU - Milligan, Graeme
AU - López-Giménez, Juan F.
AU - Robakis, Nikolaos K.
AU - Logothetis, Diomedes E.
AU - Meana, J. Javier
AU - González-Maeso, Javier
N1 - Funding Information:
We thank M. Fribourg for critical review of the manuscript, J. M. Eltit for insightful discussions, H. Vaananen for assistance with GIRK current graph preparation, R. Huq for help in Ca2+ signaling assays at the Microscopy Core, J. Gingrich for the gift of 5-HT2A knockout mice, and the staff members of the Basque Institute of Legal Medicine for their cooperation in the study. This work was supported, in whole or in part, by the NIH grants R01MH084894 and R56MH084894 (to J.G.-M.), R01HL59949 (to D.E.L.), R37AG017926 and R01AG008200 (to N.K.R.), R01DA025036 and R01DA027460 (to J.A.M.), R01NS047229 and P50AG05138 (to A.G.), and S10RR027411 (to M.C.). This work was also supported by Dainippon Sumitomo Pharma (to J.G.-M.), Spanish MINECO/EDR Funds SAF2009-68460 and SAF2013-48586R (to J.J.M.), the Basque Government (to J.J.M.), the Spanish Government SAF2010-15663 grant (MICINN) (to J.F.L.G.), and Medical Research Council (UK) grants MR/L023806/1 and G0900050 (to G.M.). P.M.-A. and A.G.-B. were recipients of predoctoral fellowships from UPV/EHU and the Basque Government in Spain, respectively.
PY - 2016/1/12
Y1 - 2016/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84955157693&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aab0467
DO - 10.1126/scisignal.aab0467
M3 - Article
C2 - 26758213
AN - SCOPUS:84955157693
SN - 1945-0877
VL - 9
JO - Science signaling
JF - Science signaling
IS - 410
ER -