Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs

Miguel Fribourg; José L. Moreno; Terrell Holloway; Davide Provasi; Lia Baki; Rahul Mahajan; Gyu Park; Scott K. Adney; Candice Hatcher; José M. Eltit; Jeffrey D. Ruta; Laura Albizu; Zheng Li; Adrienne Umali; Jihyun Shim; Alexandre Fabiato; Alexander D. MacKerell; Vladimir Brezina; Stuart C. Sealfon; Marta Filizola; Javier González-Maeso; Diomedes E. Logothetis

doi:10.1016/j.cell.2011.09.055

Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs

Miguel Fribourg, José L. Moreno, Terrell Holloway, Davide Provasi, Lia Baki, Rahul Mahajan, Gyu Park, Scott K. Adney, Candice Hatcher, José M. Eltit, Jeffrey D. Ruta, Laura Albizu, Zheng Li, Adrienne Umali, Jihyun Shim, Alexandre Fabiato, Alexander D. MacKerell, Vladimir Brezina, Stuart C. Sealfon, Marta FilizolaJavier González-Maeso^*, Diomedes E. Logothetis

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

256 Scopus citations

Abstract

Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT_2A G protein-coupled receptor (GPCR), the 2AR, which signals via a G_q heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G_i-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi-and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.

Original language	English (US)
Pages (from-to)	1011-1023
Number of pages	13
Journal	Cell
Volume	147
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2011.09.055
State	Published - Nov 23 2011

Funding

The authors thank Sophia Gruszecki, Heikki Vaananen, Dr. Jian Yang, and Dr. Basil Hanss for Xenopus oocyte isolation and are grateful to Dr. Kurt Hauser for his support with the cortical primary neuronal cultures and Dr. J.A. Gingrich for his gift of 5HT2A-KO mice. The authors are also thankful to Drs. M. Scott Bowers, Louis J. De Felice, Frank Guarnieri (Virginia Commonwealth University), Lakshmi Devi (Mount Sinai School of Medicine), Jonathan Javitch (Columbia University), George Liapakis (University of Crete, Greece), and Herbert Meltzer (Vanderbilt University) for critical feedback on the manuscript and to members of the Logothetis lab for useful feedback throughout this project. D.E.L. was partly supported for this work by NIH grant HL59949. J.G.-M. was supported by NIH grant 5R01MH084894, as well as NARSAD, Dainippon Sumitomo Pharma, and the Maltz Family Foundation Award. M.F. was supported by NIH grants MH084894, MH091360, and DA026434. The computations were supported in part by the National Science Foundation through TeraGrid advanced computing resources provided by the Texas Advanced Computing Center under grant TG-MCB080109N. J.L.M. was the recipient of a postdoctoral fellowship from Ministerio de Ciencia e Innovación, Spain. R.M. was supported by NIH grant F30HL097582. J.M.E. was supported by NIH grants SRC1DA02811202 and 1R01DA02694702.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2011.09.055

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Fribourg, M., Moreno, J. L., Holloway, T., Provasi, D., Baki, L., Mahajan, R., Park, G., Adney, S. K., Hatcher, C., Eltit, J. M., Ruta, J. D., Albizu, L., Li, Z., Umali, A., Shim, J., Fabiato, A., MacKerell, A. D., Brezina, V., Sealfon, S. C., ... Logothetis, D. E. (2011). Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs. Cell, 147(5), 1011-1023. https://doi.org/10.1016/j.cell.2011.09.055

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title = "Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs",

abstract = "Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT2A G protein-coupled receptor (GPCR), the 2AR, which signals via a Gq heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the Gi-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi-and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.",

author = "Miguel Fribourg and Moreno, {Jos{\'e} L.} and Terrell Holloway and Davide Provasi and Lia Baki and Rahul Mahajan and Gyu Park and Adney, {Scott K.} and Candice Hatcher and Eltit, {Jos{\'e} M.} and Ruta, {Jeffrey D.} and Laura Albizu and Zheng Li and Adrienne Umali and Jihyun Shim and Alexandre Fabiato and MacKerell, {Alexander D.} and Vladimir Brezina and Sealfon, {Stuart C.} and Marta Filizola and Javier Gonz{\'a}lez-Maeso and Logothetis, {Diomedes E.}",

note = "Funding Information: The authors thank Sophia Gruszecki, Heikki Vaananen, Dr. Jian Yang, and Dr. Basil Hanss for Xenopus oocyte isolation and are grateful to Dr. Kurt Hauser for his support with the cortical primary neuronal cultures and Dr. J.A. Gingrich for his gift of 5HT2A-KO mice. The authors are also thankful to Drs. M. Scott Bowers, Louis J. De Felice, Frank Guarnieri (Virginia Commonwealth University), Lakshmi Devi (Mount Sinai School of Medicine), Jonathan Javitch (Columbia University), George Liapakis (University of Crete, Greece), and Herbert Meltzer (Vanderbilt University) for critical feedback on the manuscript and to members of the Logothetis lab for useful feedback throughout this project. D.E.L. was partly supported for this work by NIH grant HL59949. J.G.-M. was supported by NIH grant 5R01MH084894, as well as NARSAD, Dainippon Sumitomo Pharma, and the Maltz Family Foundation Award. M.F. was supported by NIH grants MH084894, MH091360, and DA026434. The computations were supported in part by the National Science Foundation through TeraGrid advanced computing resources provided by the Texas Advanced Computing Center under grant TG-MCB080109N. J.L.M. was the recipient of a postdoctoral fellowship from Ministerio de Ciencia e Innovaci{\'o}n, Spain. R.M. was supported by NIH grant F30HL097582. J.M.E. was supported by NIH grants SRC1DA02811202 and 1R01DA02694702. ",

year = "2011",

month = nov,

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doi = "10.1016/j.cell.2011.09.055",

language = "English (US)",

volume = "147",

pages = "1011--1023",

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Fribourg, M, Moreno, JL, Holloway, T, Provasi, D, Baki, L, Mahajan, R, Park, G, Adney, SK, Hatcher, C, Eltit, JM, Ruta, JD, Albizu, L, Li, Z, Umali, A, Shim, J, Fabiato, A, MacKerell, AD, Brezina, V, Sealfon, SC, Filizola, M, González-Maeso, J & Logothetis, DE 2011, 'Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs', Cell, vol. 147, no. 5, pp. 1011-1023. https://doi.org/10.1016/j.cell.2011.09.055

TY - JOUR

T1 - Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs

AU - Fribourg, Miguel

AU - Moreno, José L.

AU - Holloway, Terrell

AU - Provasi, Davide

AU - Baki, Lia

AU - Mahajan, Rahul

AU - Park, Gyu

AU - Adney, Scott K.

AU - Hatcher, Candice

AU - Eltit, José M.

AU - Ruta, Jeffrey D.

AU - Albizu, Laura

AU - Li, Zheng

AU - Umali, Adrienne

AU - Shim, Jihyun

AU - Fabiato, Alexandre

AU - MacKerell, Alexander D.

AU - Brezina, Vladimir

AU - Sealfon, Stuart C.

AU - Filizola, Marta

AU - González-Maeso, Javier

AU - Logothetis, Diomedes E.

N1 - Funding Information: The authors thank Sophia Gruszecki, Heikki Vaananen, Dr. Jian Yang, and Dr. Basil Hanss for Xenopus oocyte isolation and are grateful to Dr. Kurt Hauser for his support with the cortical primary neuronal cultures and Dr. J.A. Gingrich for his gift of 5HT2A-KO mice. The authors are also thankful to Drs. M. Scott Bowers, Louis J. De Felice, Frank Guarnieri (Virginia Commonwealth University), Lakshmi Devi (Mount Sinai School of Medicine), Jonathan Javitch (Columbia University), George Liapakis (University of Crete, Greece), and Herbert Meltzer (Vanderbilt University) for critical feedback on the manuscript and to members of the Logothetis lab for useful feedback throughout this project. D.E.L. was partly supported for this work by NIH grant HL59949. J.G.-M. was supported by NIH grant 5R01MH084894, as well as NARSAD, Dainippon Sumitomo Pharma, and the Maltz Family Foundation Award. M.F. was supported by NIH grants MH084894, MH091360, and DA026434. The computations were supported in part by the National Science Foundation through TeraGrid advanced computing resources provided by the Texas Advanced Computing Center under grant TG-MCB080109N. J.L.M. was the recipient of a postdoctoral fellowship from Ministerio de Ciencia e Innovación, Spain. R.M. was supported by NIH grant F30HL097582. J.M.E. was supported by NIH grants SRC1DA02811202 and 1R01DA02694702.

PY - 2011/11/23

Y1 - 2011/11/23

N2 - Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT2A G protein-coupled receptor (GPCR), the 2AR, which signals via a Gq heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the Gi-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi-and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.

AB - Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT2A G protein-coupled receptor (GPCR), the 2AR, which signals via a Gq heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the Gi-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi-and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.

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U2 - 10.1016/j.cell.2011.09.055

DO - 10.1016/j.cell.2011.09.055

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AN - SCOPUS:81855189491

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VL - 147

SP - 1011

EP - 1023

JO - Cell

JF - Cell

IS - 5

ER -

Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs

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