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β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.

Publication ,  Journal Article
Stoppel, LJ; Auerbach, BD; Senter, RK; Preza, AR; Lefkowitz, RJ; Bear, MF
Published in: Cell Rep
March 21, 2017

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 (mGlu5), yet how mGlu5 couples to the intracellular signaling pathways that regulate mRNA translation is poorly understood. Here, we provide evidence that β-arrestin2 mediates mGlu5-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 mGlu5 inhibitors and does not affect Gq signaling. Thus, in addition to identifying a key requirement for mGlu5-stimulated protein synthesis, these data suggest that β-arrestin2-biased negative modulators of mGlu5 offer significant advantages over first-generation inhibitors for the treatment of FX and related disorders.

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Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

March 21, 2017

Volume

18

Issue

12

Start / End Page

2807 / 2814

Location

United States

Related Subject Headings

  • beta-Arrestin 2
  • Signal Transduction
  • Receptor, Metabotropic Glutamate 5
  • Protein Biosynthesis
  • Neurons
  • Neuronal Plasticity
  • Mutation
  • Molecular Targeted Therapy
  • Mice, Inbred C57BL
  • Male
 

Citation

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Stoppel, L. J., Auerbach, B. D., Senter, R. K., Preza, A. R., Lefkowitz, R. J., & Bear, M. F. (2017). β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X. Cell Rep, 18(12), 2807–2814. https://doi.org/10.1016/j.celrep.2017.02.075
Stoppel, Laura J., Benjamin D. Auerbach, Rebecca K. Senter, Anthony R. Preza, Robert J. Lefkowitz, and Mark F. Bear. “β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X.Cell Rep 18, no. 12 (March 21, 2017): 2807–14. https://doi.org/10.1016/j.celrep.2017.02.075.
Stoppel LJ, Auerbach BD, Senter RK, Preza AR, Lefkowitz RJ, Bear MF. β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X. Cell Rep. 2017 Mar 21;18(12):2807–14.
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 Rep, vol. 18, no. 12, Mar. 2017, pp. 2807–14. Pubmed, doi:10.1016/j.celrep.2017.02.075.
Stoppel LJ, Auerbach BD, Senter RK, Preza AR, Lefkowitz RJ, Bear MF. β-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X. Cell Rep. 2017 Mar 21;18(12):2807–2814.
Journal cover image

Published In

Cell Rep

DOI

EISSN

2211-1247

Publication Date

March 21, 2017

Volume

18

Issue

12

Start / End Page

2807 / 2814

Location

United States

Related Subject Headings

  • beta-Arrestin 2
  • Signal Transduction
  • Receptor, Metabotropic Glutamate 5
  • Protein Biosynthesis
  • Neurons
  • Neuronal Plasticity
  • Mutation
  • Molecular Targeted Therapy
  • Mice, Inbred C57BL
  • Male