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First published on January 18, 2007; DOI: 10.1124/mol.106.028399

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Received for publication June 28, 2006.
Revised January 5, 2007.
Accepted for publication January 5, 2007.

In vivo Regulation of Homer1a Expression in the Striatum by Cocaine

Guochi Zhang 1, Limin Mao 1, Xianyu Liu 1, Nikhil Parelkar 1, Anish Arora 1, Lu Yang 1, Eugene E Fibuch 1, John Q. Wang 2*

1 University of Missouri-Kansas City School of Medicine 2 University of Missouri-Kansas City

* Address correspondence to: E-mail: wangjq{at}umkc.edu

Abstract

The glutamate receptor adaptor protein Homer is concentrated in the postsynaptic density of excitatory synapses and is critical for normal operation of synaptic transmission. In this study, we investigated the responsiveness of Homer family proteins to dopamine stimulation with the psychostimulant cocaine in rat striatal neurons both in vivo and in vitro. We found that a single dose of cocaine specifically induced a rapid and transient increase in protein levels of the Homer1a, but not Homer1b/c and Homer2a/b, isoforms in the striatum. This selective Homer1a induction was mediated primarily through activation of dopamine D1, but not D2, receptors. Both protein kinase A and Ca2+/calmodulin-dependent protein kinases are important for mediating the cocaine stimulation of Homer1a expression. At the transcriptional level, cAMP response element-binding protein (CREB) serves as a prime transcription factor transmitting the signals derived from D1 receptors and associative pathways to the CaCRE sites within the Homer1a promoter. Functionally, noncrosslinking Homer1a, once induced, competed with the crosslinking isoforms of Homer proteins (Homer1b/c and Homer2a/b) to uncouple the connection of group I metabotropic glutamate receptors (mGluRs) with inositol-1,4,5-triphosphate (IP3) receptors. These results indicate that cocaine possesses the ability to stimulate Homer1a expression in striatal neurons through a specific synapse-to-nucleus pathway. Moreover, inducible Homer1a expression may represent a transcription-dependent mechanism underlying the dynamic regulation of submembranous macromolecular complex formation between group I mGluRs and their anchoring proteins.


Key words: Dopamine, Metabotropic glutamate, Glutamate, CREB, Cocaine, Synaptic plasticity


This article has been cited by other articles:


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[Abstract] [Full Text] [PDF]


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