β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X
Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local protein synthesis via activation of metabotropi...
| Main Authors: | , , , , , |
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| Format: | Article |
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Elsevier
2017
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| Online Access: | http://hdl.handle.net/1721.1/111663 https://orcid.org/0000-0001-6673-4988 |
| _version_ | 1826211153325326336 |
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| author | Auerbach, Benjamin D. Lefkowitz, Robert J. Stoppel, Laura Jane Senter, Rebecca K Preza, Anthony R. Bear, Mark |
| author2 | Picower Institute for Learning and Memory |
| author_facet | Picower Institute for Learning and Memory Auerbach, Benjamin D. Lefkowitz, Robert J. Stoppel, Laura Jane Senter, Rebecca K Preza, Anthony R. Bear, Mark |
| author_sort | Auerbach, Benjamin D. |
| collection | MIT |
| description | Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local protein synthesis via activation of metabotropic glutamate receptor 5 (mGlu 5 ), yet how mGlu 5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu 5 -stimulated protein synthesis in the hippocampus and show that genetic reduction of β-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr1 −/y mouse model of FX. Importantly, reducing β-arrestin2 does not induce psychotomimetic activity associated with full mGlu 5 inhibitors and does not affect G q signaling. Thus, in addition to identifying a key requirement for mGlu 5 -stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu 5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders. |
| first_indexed | 2024-09-23T15:01:26Z |
| format | Article |
| id | mit-1721.1/111663 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T15:01:26Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/1116632022-09-29T12:09:15Z β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X Auerbach, Benjamin D. Lefkowitz, Robert J. Stoppel, Laura Jane Senter, Rebecca K Preza, Anthony R. Bear, Mark Picower Institute for Learning and Memory Stoppel, Laura Jane Senter, Rebecca K Preza, Anthony R. Bear, Mark Synaptic protein synthesis is essential for modification of the brain by experience and is aberrant in several genetically defined disorders, notably fragile X (FX), a heritable cause of autism and intellectual disability. Neural activity directs local protein synthesis via activation of metabotropic glutamate receptor 5 (mGlu 5 ), yet how mGlu 5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu 5 -stimulated protein synthesis in the hippocampus and show that genetic reduction of β-arrestin2 corrects aberrant synaptic plasticity and cognition in the Fmr1 −/y mouse model of FX. Importantly, reducing β-arrestin2 does not induce psychotomimetic activity associated with full mGlu 5 inhibitors and does not affect G q signaling. Thus, in addition to identifying a key requirement for mGlu 5 -stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu 5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders. National Institutes of Health (U.S.) (Grant R21NS087225) National Institutes of Health (U.S.) (Grant 2R01HD046943) National Institutes of Health (U.S.) (Grant R01MH106469) 2017-09-29T19:28:31Z 2017-09-29T19:28:31Z 2017-03 2017-01 2017-09-27T14:23:51Z Article http://purl.org/eprint/type/JournalArticle 2211-1247 http://hdl.handle.net/1721.1/111663 Stoppel, Laura J. et al. “β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.” Cell Reports 18, 12 (March 2017): 2807–2814 © 2017 The Author(s) https://orcid.org/0000-0001-6673-4988 http://dx.doi.org/10.1016/J.CELREP.2017.02.075 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International https://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Publisher |
| spellingShingle | Auerbach, Benjamin D. Lefkowitz, Robert J. Stoppel, Laura Jane Senter, Rebecca K Preza, Anthony R. Bear, Mark β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X |
| title | β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X |
| title_full | β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X |
| title_fullStr | β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X |
| title_full_unstemmed | β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X |
| title_short | β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X |
| title_sort | β arrestin2 couples metabotropic glutamate receptor 5 to neuronal protein synthesis and is a potential target to treat fragile x |
| url | http://hdl.handle.net/1721.1/111663 https://orcid.org/0000-0001-6673-4988 |
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