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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Stoppel, LJ; Auerbach, BD; Senter, RK; Preza, AR; Lefkowitz, RJ; Bear, MF

Published Date

  • March 2017

Published In

Volume / Issue

  • 18 / 12

Start / End Page

  • 2807 - 2814

PubMed ID

  • 28329674

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

International Standard Serial Number (ISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2017.02.075

Language

  • eng