Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling

Pin Tse Lee, Po Kuan Chao, Li Chin Ou, Jian Ying Chuang, Yen Chang Lin, Shu Chun Chen, Hsiao Fu Chang, Ping Yee Law, Horace H. Loh, Yu Sheng Chao, Tsung Ping Su, Shiu Hwa Yeh

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Abstract

Heterogeneous nuclear ribonucleoprotein K (hnRNP K) binds to the promoter region of mu-opioid receptor (MOR) to regulate its transcriptional activity. How hnRNP K contributes to the analgesic effects of morphine, however, is largely unknown. We provide evidence that morphine increases hnRNP K protein expression via MOR activation in rat primary cortical neurons and HEK-293 cells expressing MORs, without increasing mRNA levels. Using the bicistronic reporter assay, we examined whether morphine-mediated accumulation of hnRNP K resulted from translational control. We identified potential internal ribosome entry site elements located in the 5′ untranslated regions of hnRNP K transcripts that were regulated by morphine. This finding suggests that internal translation contributes to the morphine-induced accumulation of hnRNP K protein in regions of the central nervous system correlated with nociceptive and antinociceptive modulatory systems in mice. Finally, we found that down-regulation of hnRNP K mediated by siRNA attenuated morphine-induced hyperpolarization of membrane potential in AtT20 cells. Silencing hnRNP K expression in the spinal cord increased nociceptive sensitivity in wild-type mice, but not in MOR-knockout mice. Thus, our findings identify the role of translational control of hnRNP K in morphine-induced analgesia through activation of MOR.

Original languageEnglish (US)
Pages (from-to)13012-13025
Number of pages14
JournalNucleic acids research
Volume42
Issue number21
DOIs
StatePublished - Dec 1 2014

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Lee, P. T., Chao, P. K., Ou, L. C., Chuang, J. Y., Lin, Y. C., Chen, S. C., Chang, H. F., Law, P. Y., Loh, H. H., Chao, Y. S., Su, T. P., & Yeh, S. H. (2014). Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling. Nucleic acids research, 42(21), 13012-13025. https://doi.org/10.1093/nar/gku1016