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J. Biol. Chem., Vol. 283, Issue 1, 582-592, January 4, 2008

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Arc/Arg3.1 Translation Is Controlled by Convergent N-Methyl-D-aspartate and G_s-coupled Receptor Signaling Pathways^*

From the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Arc/Arg3.1 is an immediate early gene whose expression is necessary for the late-phase of long-term potentiation (LTP) and memory consolidation. Whereas pathways regulating Arc transcription have been extensively investigated, less is known about the role of post-transcriptional mechanisms in Arc expression. Fluorescence microscopy experiments in cultured hippocampal neurons revealed that Arc protein level was dramatically increased by activation of the cAMP-dependent protein kinase (PKA) pathway, which is implicated in long-term memory. A PKA-dependent increase in Arc protein level was observed after pharmacological or synaptic activation of N-methyl-D-aspartate (NMDA) receptors, which play a critical role in both LTP induction and learning. Arc protein was also up-regulated by activation of PKA through G_s-coupled dopamine and β-adrenergic receptors, which regulate the late-phase of LTP and memory. When agonists for the NMDA and G_s-coupled receptors were co-applied, they had an additive effect on Arc protein expression. Interestingly, G_s-coupled receptor stimulation was ineffective in the presence of an NMDA receptor antagonist, suggesting calcium influx through the NMDA receptor plays a gating role in this pathway. Stimulation of the cAMP/PKA pathway did not affect Arc mRNA level or protein stability, identifying translational efficacy as the main determinant of Arc protein expression level. It is concluded that efficient Arc translation requires NMDA receptor activity, whereas a further enhancement can be achieved with activation of G_s-coupled receptors. These experiments have, therefore, revealed remarkable similarities in the signaling pathways that control Arc expression and those that regulate LTP, learning, and memory.

Received for publication, March 22, 2007 , and in revised form, August 7, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Duke University Medical Center, P. O. Box 3813, Durham, NC 27710. Tel.: 919-681-4862; Fax: 919-681-8461; E-mail: vando005{at}mc.duke.edu.

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