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Cocaine Induces Nuclear Export and Degradation of Neuronal Retinoid X Receptor-γ via a TNF-α/JNK- Mediated Mechanism

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Abstract

Cocaine abuse represents an immense societal health and economic burden for which no effective treatment currently exists. Among the numerous intracellular signaling cascades impacted by exposure to cocaine, increased and aberrant production of pro-inflammatory cytokines in the CNS has been observed. Additionally, we have previously reported a decrease in retinoid-X-receptor-gamma (RXR-γ) in brains of mice chronically exposed to cocaine. Through obligate heterodimerization with a number of nuclear receptors, RXRs serve as master regulatory transcription factors, which can potentiate or suppress expression of a wide spectrum of genes. Little is known about the regulation of RXR levels, but previous studies indicate cellular stressors such as cytokines negatively regulate levels of RXRs in vitro. To evaluate the mechanism underlying the cocaine-induced decreases in RXR-γ levels observed in vivo, we exposed neurons to cocaine in vitro and examined pathways which may contribute to disruption in RXR signaling, including activation of stress pathways by cytokine induction. In these studies, we provide the first evidence that cocaine exposure disrupts neuronal RXR-γ signaling in vitro by promoting its nuclear export and degradation. Furthermore, we demonstrate this effect may be mediated, at least in part, by cocaine-induced production of TNF-α and its downstream effector c-Jun-NH-terminal kinase (JNK). Findings from this study are therefore applicable to both cocaine abuse and to pathological conditions characterized by neuroinflammatory factors, such as neurodegenerative disease.

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Abbreviations

RXR-γ:

retinoid-X-receptor-gamma

JNK:

c-Jun-NH-terminal kinase

p-JNK:

phosphorylated JNK

TNF-α:

tumor-necrosis-factor-alpha

Bort:

Bortezomib

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Acknowledgments

This work was by supported in part by NIH DA029523 to TDL, and Temple University’s Comprehensive NeuroAIDS Center P30 MH092177.

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The authors declare that they have no conflicts of interest.

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  1. Department of Neuroscience, Temple University School of Medicine, Medical Education Research Building, 3500 North Broad Street, Philadelphia, PA, 19140, USA

    Jane Kovalevich, William Yen, Ahmet Ozdemir & Dianne Langford

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  1. Jane Kovalevich
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  2. William Yen
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  3. Ahmet Ozdemir
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Correspondence to Dianne Langford.

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Supplementary Figure 1

Dopamine and forskolin do not affect RXR-γ levels. a, Representative Western blot of RXR-γ in neurons treated with 30 nm dopamine. b, densitometric quantification of a. c, Representative Western blot of RXR-γ in neurons treated with 10 μm forskolin. d, densitometric quantification of c. No significant changes were observed in levels of RXR-γ. Tubulin was used as a loading control. (GIF 96 kb)

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Kovalevich, J., Yen, W., Ozdemir, A. et al. Cocaine Induces Nuclear Export and Degradation of Neuronal Retinoid X Receptor-γ via a TNF-α/JNK- Mediated Mechanism. J Neuroimmune Pharmacol 10, 55–73 (2015). https://doi.org/10.1007/s11481-014-9573-x

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