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

Moreno, J. L. et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Science Signaling, 9(410), ra5. (doi: 10.1126/scisignal.aab0467) (PMID:26758213) (PMCID:PMC4819166)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lopez-Gimenez, Dr Juan and Milligan, Professor Graeme
Authors: Moreno, J. L., Miranda-Azpiazu, P., Garcia-Bea, A., Younkin, J., Cui, M., Kozlenkov, A., Ben-Ezra, A., Voloudakis, G., Fakira, A. K., Baki, L., Ge, Y., Georgakopoulos, A., Moron, J. A., Milligan, G., Lopez-Gimenez, J. F., Robakis, N. K., Logothetis, D. E., Meana, J. J., and Gonzalez-Maeso, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Science Signaling
Publisher:American Association for the Advancement of Science
ISSN:1945-0877
ISSN (Online):1937-9145

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
510631The organisational structure of class A GPCRs: implications for function and drug designGraeme MilliganMedical Research Council (MRC)G0900050RI NEUROSCIENCE & PSYCHOLOGY
656901The organisational structure of class A GPCRs: Implications for pharmacology, function and therapeutic regulationGraeme MilliganMedical Research Council (MRC)MR/L023806/1RI MOLECULAR CELL & SYSTEMS BIOLOGY