Par-4 is a synaptic protein that regulates neurite outgrowth by altering calcium homeostasis and transcription factor AP-1 activation.

Par-4 is a synaptic protein that regulates neurite outgrowth by altering calcium homeostasis and transcription factor AP-1 activation.

Guo Q; Xie J; Chang X; Zhang X; Du H

Brain research

2001

2001-06

Although Par-4 (prostate apoptosis response-4) is involved in initiation of neurodegenerative cascades associated with certain neurodegenerative disorders, normal physiological roles of Par-4 in neurons have remained elusive. It was recently reported that Par-4 protein levels could be regulated at translational level in synaptic terminals following apoptotic insults, suggesting that Par-4 might play a role in synaptic function. We report that Par-4 is a synaptic protein preferably localized in postsynaptic density (PSD). The expression of Par-4 in synaptosome preparations and PSDs are developmentally and regionally regulated. Synaptic Par-4 is enriched in the cerebral cortex and the hippocampus, but not in the cerebellum. In vitro as well as in vivo experiments demonstrate that the levels of synaptic Par-4 increase as the neurons mature. Overexpression of Par-4 in transfected PC12 cells inhibits nerve growth factor (NGF)-induced cellular differentiation and neurite outgrowth by a mechanism involving aberrant elevation of intracellular calcium levels and suppression of activation of the transcription factor AP-1. The actions of Par-4 were consistently blocked by co-expression of the dominant negative regulator of Par-4 activity (the leucine zipper domain of Par-4). Since the leucine zipper domain of Par-4 (Leu.zip) may mediate protein–protein interactions, the results indicate that the actions of Par-4 require its interaction with other protein(s) or dimerization with itself. These results suggest that Par-4 may play an important role in postsynaptic signal transduction and regulation of cellular pathways associated with cellular differentiation and neurite outgrowth. Identification of Par-4 as a novel synaptic protein may have significant implications in understanding the mechanisms of synaptic functions in physiological and pathological settings.

*Intracellular Signaling Peptides and Proteins; Animals; Antibodies; Apoptosis Regulatory Proteins; Calcium Signaling/*physiology; Calcium/*metabolism; Carrier Proteins/genetics/immunology/*metabolism; Cell Compartmentation/physiology; Cerebral Cortex/cytology; Gene Expression/physiology; Hippocampus/cytology; Homeostasis/physiology; Inbred C57BL; Mice; Nerve Growth Factor/pharmacology; Neurites/*metabolism; Neurons/metabolism/ultrastructure; PC12 Cells; Rats; Synaptosomes/metabolism; Transcription Factor AP-1/*metabolism; Transcriptional Activation/drug effects/physiology; Transfection

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