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The Journal of Neuroscience, October 12, 2005, 25(41):9488-9496; doi:10.1523/JNEUROSCI.2450-05.2005

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Development/Plasticity/Repair
The Nonkinase Phorbol Ester Receptor 1-Chimerin Binds the NMDA Receptor NR2A Subunit and Regulates Dendritic Spine Density

Thomas J. Van de Ven, Hendrika M. A. VanDongen, and Antonius M. J. VanDongen

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

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 1-chimerin is present in dendrites and spines, where it binds to the NMDA receptor NR2A subunit in a phorbol ester-dependent manner. 1-Chimerin contains a GTPase activating (GAP) domain, with activity toward the Rho family member Rac1. Overexpression of 1-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 1-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 1-chimerin to modulate spine number requires an interaction with the NMDA receptor, because an 1-chimerin mutant that binds weakly to NR2A fails to decrease spine density. Together, these results suggest that 1-chimerin is able to modulate dendritic spine morphology by binding to synaptic NMDA receptors and locally inactivating Rac1.

Key words: NMDA receptors; -chimerin; Rho GTPases; dendritic spines; phorbol ester receptors; GTPase activating proteins

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Received June 15, 2005; revised August 23, 2005; accepted August 23, 2005.

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