ESRRG-controlled downregulation of KCNN1 in primary sensory neurons is required for neuropathic pain
Huixing Wang, … , Huijuan Hu, Yuan-Xiang Tao
Huixing Wang, … , Huijuan Hu, Yuan-Xiang Tao
Published June 24, 2024
Citation Information: JCI Insight. 2024;9(12):e180085. https://doi.org/10.1172/jci.insight.180085.
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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 4

Effect of rescuing KCNN1 downregulation in the injured DRG on the maintenance of CCI-induced nociceptive hypersensitivity in male mice.

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Effect of rescuing KCNN1 downregulation in the injured DRG on the mainte...
The mice were microinjected with AAV9-KCNN1 or AAV9-GFP into the ipsilateral L3/4 DRGs 14 days before CCI. (A–D) Paw withdrawal frequencies (PWF) in response to 0.07 g (A) and 0.4 g (B) von Frey filament stimuli and paw withdrawal latencies (PWL) to heat (C) and cold (D) stimuli on the ipsilateral and contralateral sides at the different days as indicated after CCI. n = 8 mice/group. **P < 0.01 versus the AAV5-GFP–microinjected CCI group at the corresponding days on the ipsilateral side by 3-way ANOVA with repeated measures followed by post hoc Tukey test. (E and F) Spontaneous nociceptive responses as assessed by the conditioned place preference (CPP) paradigm on day 28 after CCI. The time spent in each chamber (E) and difference scores for chamber preferences calculated by subtracting preconditioning (Pre) preference time from postconditioning (Post) time spent in the lidocaine-paired chamber (F). n = 8 mice/group. **P < 0.01 by 2-way ANOVA with repeated measures followed by post hoc Tukey test (E) or by 2-tailed unpaired Student’s t test (F). (G–I) Expression of p-ERK1/2 (G), total ERK1/2 (G), GFAP (G), Iba1 (H and I), and CD68 (H and I) protein in the ipsilateral L3/4 dorsal horn on day 28 after CCI or from naive mice. n = 3 biological repeats (6 mice)/group. **P < 0.01 by 1-way ANOVA followed by post hoc Tukey test. (J) Expression of KCNN1 in the ipsilateral L3/4 DRGs on day 28 after CCI or from naive mice. n = 3 repeats (6 mice)/group. **P < 0.01 by 1-way ANOVA followed by post hoc Tukey test.