Actinin-4 Governs Dendritic Spine Dynamics and Promotes Their Remodeling by Metabotropic Glutamate Receptors

J Biol Chem. 2015 Jun 26;290(26):15909-20. doi: 10.1074/jbc.M115.640136. Epub 2015 May 5.

Abstract

Dendritic spines are dynamic, actin-rich protrusions in neurons that undergo remodeling during neuronal development and activity-dependent plasticity within the central nervous system. Although group 1 metabotropic glutamate receptors (mGluRs) are critical for spine remodeling under physiopathological conditions, the molecular components linking receptor activity to structural plasticity remain unknown. Here we identify a Ca(2+)-sensitive actin-binding protein, α-actinin-4, as a novel group 1 mGluR-interacting partner that orchestrates spine dynamics and morphogenesis in primary neurons. Functional silencing of α-actinin-4 abolished spine elongation and turnover stimulated by group 1 mGluRs despite intact surface receptor expression and downstream ERK1/2 signaling. This function of α-actinin-4 in spine dynamics was underscored by gain-of-function phenotypes in untreated neurons. Here α-actinin-4 induced spine head enlargement, a morphological change requiring the C-terminal domain of α-actinin-4 that binds to CaMKII, an interaction we showed to be regulated by group 1 mGluR activation. Our data provide mechanistic insights into spine remodeling by metabotropic signaling and identify α-actinin-4 as a critical effector of structural plasticity within neurons.

Keywords: Ca2+/calmodulin-dependent protein kinase II (CaMKII); actin-binding proteins; actinin; dendritic protrusion dynamics; dendritic spine; metabotropic glutamate receptor (mGluR); neuron; synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinin / genetics
  • Actinin / metabolism*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cells, Cultured
  • Dendritic Spines / genetics
  • Dendritic Spines / metabolism*
  • Female
  • Humans
  • Male
  • Mice
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Binding
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*

Substances

  • ACTN4 protein, human
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Actinin
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2