Allosteric signaling through an mGlu2 and 5-HT2Aheteromeric receptor complex and its potential contribution to schizophrenia
Year: 2016
Type: article
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.
Source: Science Signaling
Authors: 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
Institutions: Virginia Commonwealth University, Icahn School of Medicine at Mount Sinai, University of the Basque Country, Centro de Investigación Biomédica en Red de Salud Mental, Columbia University Irving Medical Center, Columbia University, University of Glasgow, Consejo Superior de Investigaciones Científicas, Instituto de Biomedicina y Biotecnología de Cantabria, BioCruces Health research Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Dainippon Sumitomo Pharma, Eusko Jaurlaritza, National Institutes of Health, Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Neurological Disorders and Stroke, National Center for Research Resources
Awards: G1228824270, G1612041964, G1989540312, G1998448681, G2121117207, The organisational structure of class A GPCRs: Implications for pharmacology, function and therapeutic regulation, G3028223774, G4413538008, High Performance Computing Cluster for Biomedical Research at VCU, G472982855, AMPA receptors: Common role in opiate withdrawal and pain sensitivity, Structure and function of the 5HT2A-mGlu2 heteromer in schizophrenia, G6921981647, G8183245202, G9000016020, G9000034517, G9000123778, G9000131702, G9000285675, G9000354132, Structural Determinants of PIP2 Regulation, G92896382
OpenAlex ID: W2232768025