MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Molecular Pharmacology Fast Forward
First published on December 12, 2006; DOI: 10.1124/mol.106.026351

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
mol.106.026351v1
71/3/835    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wei, Y.
Right arrow Articles by Saunders, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wei, Y.
Right arrow Articles by Saunders, C.


Received for publication May 5, 2006.
Revised December 6, 2006.
Accepted for publication December 6, 2006.

DOPAMINE TRANSPORTER ACTIVITY MEDIATES AMPHETAMINE-INDUCED INHIBITION OF AKT THROUGH A CaMKII-DEPENDENT MECHANISM

Yuqiang Wei 1, Jason Williams 2, Concetta Dipace 2, Uhna Sung 2, Jonathan Javitch 3, Aurelio Galli 4*, Christine Saunders 5

1 UCSF 2 Vanderbilt 3 Columbia University 4 vanderbilt university 5 Vanderbilt University Medical Center

* Address correspondence to: E-mail: aurelio.galli{at}vanderbilt.edu

Abstract

The primary mechanism for clearance of extracellular dopamine (DA) is uptake mediated by the dopamine transporter (DAT), which is governed, in part, by the number of functional DATs on the cell surface. Previous studies have shown that amphetamine (AMPH) decreases DAT cell surface expression, whereas insulin reverses this effect through the action of phosphatidylinositol 3-kinase (PI3K). Therefore, it is possible that AMPH causes DAT cell surface redistribution by inhibiting basal insulin signaling. Here, we show in a heterologous expression system and in murine striatal synaptosomes that AMPH causes a time-dependent decrease in the activity of Akt, a protein kinase immediately downstream of PI3K. This effect was blocked by the DAT inhibitor cocaine, suggesting that AMPH must interact with DAT in order to inhibit Akt. We also showed that AMPH is able to stimulate Ca2+/calmodulin-dependent kinase II (CaMKII) activity, both in the heterologous expression system as well as in murine striatal synaptosomes. The ability of AMPH to decrease Akt activity was blocked by the CaMKII inhibitor KN93, but not by its inactive analog KN92. Furthermore, preincubation with KN93 prevented the AMPH-induced decrease in DAT cell surface expression. Thus, AMPH, but not cocaine, decreases Akt activity through a CaMKII-dependent pathway, thereby providing a novel mechanism by which AMPH regulates insulin signaling and DAT trafficking.


Key words: Dopamine, Biogenic Amine, Amphetamines


This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
F. Binda, C. Dipace, E. Bowton, S. D. Robertson, B. J. Lute, J. U. Fog, M. Zhang, N. Sen, R. J. Colbran, M. E. Gnegy, et al.
Syntaxin 1A Interaction with the Dopamine Transporter Promotes Amphetamine-Induced Dopamine Efflux
Mol. Pharmacol., October 1, 2008; 74(4): 1101 - 1108.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
K. Erreger, C. Grewer, J. A. Javitch, and A. Galli
Currents in Response to Rapid Concentration Jumps of Amphetamine Uncover Novel Aspects of Human Dopamine Transporter Function
J. Neurosci., January 23, 2008; 28(4): 976 - 989.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2006 by the American Society for Pharmacology and Experimental Therapeutics