Remodeling of the Postsynaptic Density: A Macromolecular Signaling Complex

Abstract

The postsynaptic density (PSD), a macromolecular protein machine that resides under the postsynaptic plasma membrane, regulates the efficiency of synaptic transmission by stabilizing neurotransmitter receptors in the membrane and organizing signaling molecules within the postsynaptic compartment. Data suggests that synaptic activity results in changes in the protein composition of the PSD and it is hypothesized that these changes lead to structural modifications that explain enduring and stable alterations in synaptic function. However, direct evidence for these structural changes has never been obtained and the extent of remodeling and the mechanisms responsible are not fully understood. Our long term goal is to create a high-resolution molecular model of the PSD that accurately represents the number and 3D relationships between its protein components allowing hypothesis to be generated about how recruitment or loss of specific proteins results in structural alterations at the PSD. The ubiquitin proteasome system (UPS) targets proteins for degradation and is, in part, responsible for modifications of the proteins that compose the PSD. Synaptic activity has been shown to induce proteasomal recruitment into the postsynaptic compartment, that requires prior activity-dependent recruitment of CaMKII, resulting in changes in protein composition of PSDs. Electron cryo-tomography (ECT) and immunogold labeling were employed to examine the 3D structure of isolated PSDs and to identify scaffold molecules targeted by the UPS. Proteasome levels were found to be highest in PSDs isolated earlier in development, providing evidence that the UPS plays a crucial role in the structural reorganization of PSDs. ECT will also be utilized to examine whether CaMKII functions as a direct scaffold for the proteasome that might serve as a mechanism to spatially restrict protein degradation.