The nonkinase phorbol ester receptor alpha 1-chimerin binds the NMDA receptor NR2A subunit and regulates dendritic spine density.

Published

Journal Article

Abnormalities in dendritic spines have long been associated with cognitive dysfunction and neurodevelopmental delay, whereas rapid changes in spine shape underlie synaptic plasticity. The key regulators of cytoskeletal reorganization in dendrites and spines are the Rho GTPases, which modify actin polymerization in response to synaptic signaling. Rho GTPase activity is modulated by multiple regulatory proteins, some of which have been found to associate with proteins localized to spines. Here, we show that the nonkinase phorbol ester receptor alpha1-chimerin is present in dendrites and spines, where it binds to the NMDA receptor NR2A subunit in a phorbol ester-dependent manner. Alpha1-chimerin contains a GTPase activating (GAP) domain, with activity toward the Rho family member Rac1. Overexpression of alpha1-chimerin in cultured hippocampal neurons inhibits formation of new spines and removes existing spines. This reduction in spine density is mediated by Rac1 inhibition, because it depends critically on the presence of a functional GAP domain. Conversely, depletion of alpha1-chimerin leads to an increase in spine density, indicating that a basal inhibition of Rac1 maintains the number of spines at a submaximal level. The ability of alpha1-chimerin to modulate spine number requires an interaction with the NMDA receptor, because an alpha1-chimerin mutant that binds weakly to NR2A fails to decrease spine density. Together, these results suggest that alpha1-chimerin is able to modulate dendritic spine morphology by binding to synaptic NMDA receptors and locally inactivating Rac1.

Full Text

Duke Authors

Cited Authors

  • Van de Ven, TJ; VanDongen, HMA; VanDongen, AMJ

Published Date

  • October 12, 2005

Published In

Volume / Issue

  • 25 / 41

Start / End Page

  • 9488 - 9496

PubMed ID

  • 16221859

Pubmed Central ID

  • 16221859

Electronic International Standard Serial Number (EISSN)

  • 1529-2401

Digital Object Identifier (DOI)

  • 10.1523/JNEUROSCI.2450-05.2005

Language

  • eng

Conference Location

  • United States