ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain
Huixing Wang, Wanhong Zuo, Xiaozhou Feng, Xiaodong Huo, Yingping Liang, Bing Wang, Dilip Sharma, Xiang Li, Bushra Yasin, Jiang-Hong Ye, Huijuan Hu, Yuan-Xiang Tao
Huixing Wang, Wanhong Zuo, Xiaozhou Feng, Xiaodong Huo, Yingping Liang, Bing Wang, Dilip Sharma, Xiang Li, Bushra Yasin, Jiang-Hong Ye, Huijuan Hu, Yuan-Xiang Tao
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Research Article Neuroscience

ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain

Abstract

Peripheral nerve injury–induced neuronal hyperactivity in the dorsal root ganglion (DRG) participates in neuropathic pain. The calcium-activated potassium channel subfamily N member 1 (KCNN1) mediates action potential afterhyperpolarization (AHP) and gates neuronal excitability. However, the specific contribution of DRG KCNN1 to neuropathic pain is not yet clear. We report that chronic constriction injury (CCI) of the unilateral sciatic nerve or unilateral ligation of the fourth lumbar nerve produced the downregulation of Kcnn1 mRNA and KCNN1 protein in the injured DRG. This downregulation was partially attributed to a decrease in DRG estrogen-related receptor gamma (ESRRG), a transcription factor, which led to reduced binding to the Kcnn1 promoter. Rescuing this downregulation prevented CCI-induced decreases in total potassium voltage currents and AHP currents, reduced excitability in the injured DRG neurons, and alleviated CCI-induced development and maintenance of nociceptive hypersensitivities, without affecting locomotor function and acute pain. Mimicking the CCI-induced DRG KCNN1 downregulation resulted in augmented responses to mechanical, heat, and cold stimuli in naive mice. Our findings indicate that ESRRG-controlled downregulation of DRG KCNN1 is likely essential for the development and maintenance of neuropathic pain. Thus, KCNN1 may serve as a potential target for managing this disorder.

Authors

Huixing Wang, Wanhong Zuo, Xiaozhou Feng, Xiaodong Huo, Yingping Liang, Bing Wang, Dilip Sharma, Xiang Li, Bushra Yasin, Jiang-Hong Ye, Huijuan Hu, Yuan-Xiang Tao

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Figure 6

Downregulated KCNN1 participates in the CCI-induced increase of the excitability in injured DRG neurons.

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Downregulated KCNN1 participates in the CCI-induced increase of the exci...
Recordings were conducted in the ipsilateral L3/4 DRGs 7–10 days after surgery in male mice with pre-microinjection of AAV-9-KCNN1/-GFP (KCNN1) or AAV9-GFP (GFP) into the injured DRG for 28 days. Number of the neurons recorded and number of mice used are indicated. (A) Representative traces of AHP currents. (B and C) Amplitudes of AHP currents before apamin application (B) and relative reductions in the amplitudes of AHP currents after apamin treatment (C) in small, medium, and large DRG neurons from 3 treated groups as indicated. **P < 0.01 by 2-way ANOVA with post hoc Tukey test. (D) Representative traces of total Kv current. (E and F) I–V curves before apamin application (E) and relative reductions in the amplitudes of total Kv currents (F) in small, medium, and large DRG neurons from 3 treated groups as indicated. *P < 0.05, **P < 0.01 between the GFP plus CCI mice and GFP plus sham mice or KCNN1 plus CCI mice at the corresponding voltage by 2-way ANOVA with repeated measures followed by post hoc Tukey test (E). **P < 0.01 by 2-way ANOVA with post hoc Tukey test (F). (G) Representative traces of action potentials. (H and I) The frequency of action potentials before apamin application (H) and relative increases in the frequency of action potentials after apamin treatment (I) in small, medium, and large DRG neurons from 3 treated groups as indicated. *P < 0.05, **P < 0.01 versus the GFP plus sham group at the corresponding voltage and #P < 0.05 versus the GFP plus CCI group at the corresponding voltage by 3-way ANOVA with repeated measures followed by post hoc Tukey test (H). *P < 0.05, **P < 0.01 by 2-way ANOVA with post hoc Tukey test (I).