Arc/Arg3.1 translation is controlled by convergent N-methyl-D-aspartate and Gs-coupled receptor signaling pathways.

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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 beta-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.





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Bloomer, Wendy AC, Hendrika MA VanDongen and Antonius MJ VanDongen (2008). Arc/Arg3.1 translation is controlled by convergent N-methyl-D-aspartate and Gs-coupled receptor signaling pathways. The Journal of biological chemistry, 283(1). pp. 582–592. 10.1074/jbc.m702451200 Retrieved from

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Antonius M. J. VanDongen

Associate Professor of Pharmacology & Cancer Biology

We have discovered a new connection between the memory gene Arc (Activity Regulated, Cytoskeletal-associated protein) and Alzheimer's disease. Arc is a master regulator of of synaptic plasticity and epigenetically controls the transcription of 1900 genes associated with with synaptic function, neuronal plasticity, intrinsic excitability (channels, receptors, transporters), and signaling pathways (transcription factors/regulators). Approximately 100 genes whose activity-dependent expression level depends on Arc are associated with the pathophysiology of Alzheimer’s disease, suggesting a critical role for Arc in the development of neurodegenerative disorders.

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