Cell Reports
Volume 29, Issue 2, 8 October 2019, Pages 258-269.e8
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Shank Proteins Couple the Endocytic Zone to the Postsynaptic Density to Control Trafficking and Signaling of Metabotropic Glutamate Receptor 5

https://doi.org/10.1016/j.celrep.2019.08.102Get rights and content
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Highlights

  • Receptor activation triggers efficient internalization of mGluR5 in spines

  • Shank proteins control mGluR5 trafficking and signaling

  • Shanks link essential components of the endocytic zone to the postsynaptic density

  • Mutation in SHANK2 found in ASD disrupt these processes

Summary

Activation of postsynaptic metabotropic glutamate receptors (mGluRs) modulates neuronal excitability and synaptic plasticity, while deregulation of mGluR signaling has been implicated in neurodevelopmental disorders. Overstimulation of mGluRs is restricted by the rapid endocytosis of receptors after activation. However, how membrane trafficking of mGluRs at synapses is controlled remains poorly defined. We find that in hippocampal neurons, the agonist-induced receptor internalization of synaptic mGluR5 is significantly reduced in Shank knockdown neurons. This is rescued by the re-expression of wild-type Shanks, but not by mutants unable to bind Homer1b/c, Dynamin2, or Cortactin. These effects are paralleled by a reduction in synapses associated with an endocytic zone. Moreover, a mutation in SHANK2 found in autism spectrum disorders (ASDs) similarly disrupts these processes. On the basis of these findings, we propose that synaptic Shank scaffolds anchor the endocytic machinery to govern the efficient trafficking of mGluR5 and to balance the surface expression of mGluRs to efficiently modulate neuronal functioning.

Keywords

metabotropic glutamate receptor
synaptic transmission
Shank
endocytosis
receptor trafficking
endocytic zone
postsynaptic density

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