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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 18, 2006; DOI: 10.1124/jpet.106.108415

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Received for publication May 25, 2006.
Revised October 11, 2006.
Accepted for publication October 17, 2006.

PKA activation downregulates whereas ERK activation upregulates sigma-1 receptors in B-104 cells: Implication for neuroplasticity

Gianfrancesco Cormaci 1, Tomohisa Mori 1, Teruo Hayashi 1, Tsung-Ping Su 2*

1 IRP, NIDA, NIH 2 IRP, NIDA/ NIH

* Address correspondence to: E-mail: tsu{at}intra.nida.nih.gov

Abstract

The sigma-1 receptor (Sig-1R) can bind psychostimulants and was shown to be upregulated in the brain of methamphetamine self-administering rats. Upregulation of Sig-1Rs has been implicated in neuroplasticity. However, the mechanism(s) whereby Sig-1Rs are upregulated by psychostimulants is unknown. Here, we employed a neuroblastoma cell line B-104, devoid of dopamine receptors and transporter, and examined the effects of psychostimulants as well as cAMP on the expression of Sig-1Rs in this cell line, with a specific goal to identify signal transduction pathway(s) that may regulate Sig-1R expression. Chronic treatments of B-104 cells with physiological concentrations of cocaine or methamphetamine failed to alter the expression of Sig-1Rs. Dibutyryl cAMP (dB-cAMP), when used at 0.5 mM, caused a downregulation of Sig-1Rs that could be blocked by a protein kinase A (PKA) inhibitor H-89. However, dB-cAMP, when used at 2 mM, caused an upregulation of Sig-1Rs that was insensitive to the H-89 blockade but was partially blocked by an extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK) inhibitor PD98059. Further, 2 mM of dB-cAMP induced an ERK phosphorylation lasting at least 90 min, at which time the phosphorylation caused by 0.5 mM of dB-cAMP had already diminished. PD98059, applied 90 min after addition of 2 mM of dB-cAMP, attenuated the Sig-1R upregulation. Our results indicate that cAMP is bimodal in regulating Sig-1R expression: a downregulation via PKA and an upregulation via ERK. Results also suggest that psychostimulants may manipulate the cAMP-PKA-Sig-1R and/or the cAMP-ERK-Sig-1R pathways to achieve a neuroplasticity that favors addictive behaviors.


Key words: Cocaine, ERK, Methamphetamine, PKA, cAMP, sigma receptor


This article has been cited by other articles:


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J. Pharmacol. Exp. Ther., October 1, 2008; 327(1): 187 - 195.
[Abstract] [Full Text] [PDF]


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