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
View: Text | PDF
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

×

Figure 7

ESRRG reduction is responsible for the CCI-induced downregulation of KCNN1 in the injured DRG.

Options: View larger image (or click on image) Download as PowerPoint
ESRRG reduction is responsible for the CCI-induced downregulation of KCN...
(A) The binding activity of ESRRG to the Kcnn1 gene promoter in the ipsilateral L3/4 DRGs 7 days postsurgery. n = 15 mice/group. **P < 0.01 by 2-tailed unpaired Student’s t test. (B) Kcnn1 promoter activity in the CAD cells treated with the vectors/siRNAs as shown. n = 3 repeats/group. **P < 0.01 by 1-way ANOVA followed by Tukey post hoc test. Naive, pGL3-Basic; Kcnn1, pGL3-Kcnn1 report vector; Esrrg si, Esrrg siRNA; Scr si, scrambled siRNA; Esrrg, vector expressing Esrrg mRNA; GFP, vector expressing GFP. (C and D) Expression of ESRRG and KCNN1 in the ipsilateral L3/4 DRGs 21 days after surgery in mice with pre-microinjection of AAV5-ESRRG (ESRRG) or AAV5-GFP (GFP). n = 6 mice/group. **P < 0.01 by 2-way ANOVA followed by post hoc Tukey test. (E and F) Expression of ESRRG and KCNN1 in the ipsilateral L3/4 DRGs 7 days after microinjection of Esrrg siRNA (ES si) or scrambled siRNA (Scr si) in mice with pre-microinjection of AAV9-KCNN1 (KCNN1) or AAV9-GFP (GFP). n = 6 mice/group. **P < 0.01 by 1-way ANOVA followed by post hoc Tukey test. (G–J) Paw withdrawal frequencies (PWF; G and H) and paw withdrawal latencies (PWL; I and J) on the days as indicated after microinjection of Esrrg siRNA (ES si) or scrambled siRNA (Scr si) in mice with pre-microinjection of AAV9-KCNN1 (KCNN1) or AAV9-GFP (GFP). n = 8 mice/group. **P < 0.01 versus the GFP plus Scr si group or #P < 0.05, ##P < 0.01 versus the GFP plus ES si group at the corresponding days by 2-way ANOVA with repeated measures followed by post hoc Tukey test. (K) Coexpression of Kcnn1 mRNA with ESRRG (arrows) in naive L4 DRG neurons. n = 3 mice.