Cell - A Prolyl-Isomerase Mediates Dopamine-Dependent Plasticity and Cocaine Motor Sensitization

Cell - A Prolyl-Isomerase Mediates Dopamine-Dependent Plasticity and Cocaine Motor Sensitization

A Prolyl-Isomerase Mediates Dopamine-Dependent Plasticity and Cocaine Motor Sensitization

• Summary
• 
• Comments (0)

  To view the full text, please login as a subscribed user or purchase a subscription. Click here to view the full text on ScienceDirect.

• Graphical Abstract

• PDF 10.78 MB
• Export Citation
• Permissions

Cell, Volume 154, Issue 3, 637-650, 1 August 2013
Copyright © 2013 Elsevier Inc. All rights reserved.
10.1016/j.cell.2013.07.001

Authors

Joo Min Park, Jia-Hua Hu, Aleksandr Milshteyn, Ping-Wu Zhang, Chester G. Moore, Sungjin Park, Michael C. Datko, Racquel D. Domingo, Cindy M. Reyes, Xiaodong J. Wang, Felicia A. Etzkorn, Bo Xiao, Karen K. Szumlinski, Dorothee Kern, David J. Linden, Paul F. WorleySee Affiliations

• Highlights
• Pin1 binds group I mGluR when phosphorylated at the Homer-binding site
• Potentiation of mGluR5-dependent NMDAR current is dependent on Pin1 isomerase
• Homer1a is required for Pin1 to bind phosphorylated mGluR5
• mGluR5-Pin1 mechanism is essential for cocaine motor sensitization

Summary

Synaptic plasticity induced by cocaine and other drugs underlies addiction. Here we elucidate molecular events at synapses that cause this plasticity and the resulting behavioral response to cocaine in mice. In response to D1-dopamine-receptor signaling that is induced by drug administration, the glutamate-receptor protein metabotropic glutamate receptor 5 (mGluR5) is phosphorylated by microtubule-associated protein kinase (MAPK), which we show potentiates Pin1-mediated prolyl-isomerization of mGluR5 in instances where the product of an activity-dependent gene, Homer1a, is present to enable Pin1-mGluR5 interaction. These biochemical events potentiate N-methyl-D-aspartate receptor (NMDAR)-mediated currents that underlie synaptic plasticity and cocaine-evoked motor sensitization as tested in mice with relevant mutations. The findings elucidate how a coincidence of signals from the nucleus and the synapse can render mGluR5 accessible to activation with consequences for drug-induced dopamine responses and point to depotentiation at corticostriatal synapses as a possible therapeutic target for treating addiction.