Positive Regulatory Domain I–binding Factor 1 Mediates Peripheral Nerve Injury–induced Nociception in Mice by Repressing Kv4.3 Channel Expression

Abstract

Background The transcriptional repressor positive regulatory domain I–binding factor 1 (PRDM1) is expressed in adult mouse dorsal root ganglion and regulates the formation and function of peripheral sensory neurons. The authors hypothesized that PRDM1 in the dorsal root ganglion may contribute to peripheral nerve injury–induced nociception regulation and that its mechanism may involve Kv4.3 channel transcriptional repression. Methods Nociception was induced in C57BL/6 mice by applying chronic constriction injury, complete Freund’s adjuvant, or capsaicin plantar injection. Nociceptive response was evaluated by mechanical allodynia, thermal hyperalgesia, cold hyperalgesia, or gait analysis. The role of PRDM1 was evaluated by injection of Prdm1 knockdown and overexpression adeno-associated viruses. The interaction of PRDM1 at the Kv4.3 (Kcnd3) promoter was evaluated by chromatin immunoprecipitation assay. Excitability of dorsal root ganglion neurons was evaluated by whole cell patch clamp recordings, and calcium signaling in spinal dorsal horn neurons was evaluated by in vivo two-photon imaging. Results Peripheral nerve injury increased PRDM1 expression in the dorsal root ganglion, which reduced the activity of the Kv4.3 promoter and repressed Kv4.3 channel expression (injured vs. uninjured; all P < 0.001). Knockdown of PRDM1 rescued Kv4.3 expression, reduced the high excitability of injured dorsal root ganglion neurons, and alleviated peripheral nerve injury–induced nociception (short hairpin RNA vs. Scram; all P < 0.05). In contrast, PRDM1 overexpression in naive mouse dorsal root ganglion neurons diminished Kv4.3 channel expression and induced hyperalgesia (PRDM1 overexpression vs. control, mean ± SD; n = 13; all P < 0.0001) as evaluated by mechanical allodynia (0.6 ± 0.3 vs. 1.2 ± 0.2 g), thermal hyperalgesia (5.2 ± 1.3 vs. 9.8 ± 1.7 s), and cold hyperalgesia (3.4 ± 0.5 vs. 5.3 ± 0.6 s). Finally, PRDM1 downregulation in naive mice reduced the calcium signaling response of spinal dorsal horn neurons to thermal stimulation. Conclusions PRDM1 contributes to peripheral nerve injury–induced nociception by repressing Kv4.3 channel expression in injured dorsal root ganglion neurons. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

E3 Ubiquitin Ligase Uhrf2 Knockout Reveals a Critical Role in Social Behavior and Synaptic Plasticity in the Hippocampus

“…A gene was considered to be expressed if it had fragments per kilobase per million greater than one. For a gene to be considered differentially expressed, it had to meet two criteria: a greater than 2.0-fold change in expression level and a p-value < 0.05 [81,82].…”

SUMOylation of the Kv4.2 Ternary Complex Increases Surface Expression and Current Amplitude by Reducing Internalization in HEK 293 Cells

“…Kv4 channels contribute to IA in the heart ( Niwa et al, 2008 ) and play a key role in shaping neuronal excitability, action potential firing rate, synaptic integration and plasticity ( Jerng et al, 2004a ). Dysregulation of Kv4 channels is associated with heart disease ( Huo et al, 2014 ) as well as with neurological disorders, including epilepsy, Alzheimer’s disease, major depressive disorder, Huntington’s disease, and chronic pain ( Hall et al, 2015 ; Scala et al, 2015 ; Kohling and Wolfart, 2016 ; Zemel et al, 2018 ; Carrillo-Reid et al, 2019 ; Noh et al, 2019 ; Aceto et al, 2020 ; Kanda et al, 2021 ; Kim et al, 2021 ; Wang et al, 2021 ).…”