Editors' ChoiceNeuroscience

Painful Long Noncoding RNA

Sci. Signal.  06 Aug 2013:
Vol. 6, Issue 287, pp. ec181
DOI: 10.1126/scisignal.2004591

Neuropathic pain and allodynia are chronic pain and pain in response to nonnoxious stimuli, respectively, that result from injury to peripheral sensory nerves and, consequently, excessive neuronal activity. Voltage-gated potassium channels serve as key gatekeepers of neuronal excitability (see Han and Jan). Zhao et al. identified a long noncoding RNA (lncRNA) transcribed in the antisense direction from the Kcna2 gene, which encodes the Kcna2 potassium channel (also known as Kv1.2) in the dorsal root ganglia (DRG) of several mammalian species, including rat and human. In situ analysis showed that this antisense transcript, which they named Kcna2 antisense RNA, was present in DRG neurons, and double labeling for Kcna2 proteins indicated an inverse relationship. The authors identified a consensus binding site for the transcription factor MZF1 in the promoter of the gene encoding Kcna2 antisense RNA, and chromatin immunoprecipitation experiments showed that MZF1 was associated with the promoter. Spinal nerve ligation increased the binding of MZF1 to the Kcna2 antisense RNA promoter, increased the staining intensity and number of neurons positive for Kcna2 antisense RNA, and reduced the abundance of Kcna2 mRNA and protein in the same neurons. Injection of a vector expressing the Kcna2 antisense RNA into DRG, along with vector expressing a fluorescent protein to mark the positive neurons, resulted in a decrease in voltage-gated potassium currents, an increase in resting membrane potentials, and an increase in evoked action potentials, indicative of increased neuronal excitability. The rats also showed increased sensitivity to cold and mechanical stimuli on the paws on the injected side. In vivo injection into the DRG of a vector containing a Kcna2 sequence that blocked the MZF1-induced increase in Kcna2 antisense RNA and reduction of Kcna2 mRNA when introduced into cultured DRG neurons blocked these two responses after nerve ligation or damage. Furthermore, the hypersensitivity responses of the rats were attenuated after nerve injury when they were injected with this Kcna2 antisense RNA–blocking vector. Thus, nerve injury increases the production of an lncRNA that reduces the abundance of a potassium channel, resulting in neuronal hyperexcitability and increased pain sensitivity.

X. Zhao, Z. Tang, H. Zhang, F. E. Atianjoh, J.-Y. Zhao, L. Liang, W. Wang, X. Guan, S.-C. Kao, V. Tiwari, Y.-J. Gao, P. N. Hoffman, H. Cui, M. Li, X. Dong, Y.-X. Tao, A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat. Neurosci. 16, 1024–1031 (2013). [PubMed]

T. W. Han, L. Y. Jan, Making antisense of pain. Nat. Neurosci. 16, 986–987 (2013). [PubMed]

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