Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons

Abstract

Epigenetic modifications are involved in the onset, development, and maintenance of pain; however, the precise epigenetic mechanism underlying pain regulation remains elusive. Here it is reported that the epigenetic factor chromodomain Y-like (CDYL) is crucial for pain processing. Selective knockout of CDYL in sensory neurons results in decreased neuronal excitability and nociception. Moreover, CDYL facilitates histone 3 lysine 27 trimethylation (H3K27me3) deposition at the Kcnb1 intron region thus silencing voltage-gated potassium channel (K v ) subfamily member K v 2.1 transcription. Loss function of CDYL enhances total K v and K v 2.1 current density in dorsal root ganglia and knockdown of K v 2.1 reverses the pain-related phenotypes of Cdyl deficiency mice. Furthermore, focal administration of a novel potent CDYL antagonist blunts nociception and attenuates neuropathic pain. These findings reveal that CDYL is a critical regulator of pain sensation and shed light on the development of novel analgesics targeting epigenetic mechanisms.

Distinct cellular expression and subcellular localization of Kv2 voltage‐gated K+ channel subtypes in dorsal root ganglion neurons conserved between mice and humans

“…Kv2 conductances modulate electrical transmission in rat DRG neurons (Tsantoulas et al., 2014). Knockdown of Kv2.1 increases hypersensitivity to painful stimuli, and regulation of Kv2.1 protein expression through the epigenetic factor Cdyl modulates neuronal excitability and nociception (Sun et al., 2022). Consistent with these studies, our results show that Kv2 channels are localized to DRG neuron axons, where they could potentially influence electrical transmission.…”

Distinct cellular expression and subcellular localization of Kv2 voltage-gated K+channel subtypes in dorsal root ganglion neurons conserved between mice and humans

“…Kv2 conductances modulate electrical transmission in rat DRG neurons (Tsantoulas et al, 2014). Knockdown of Kv2.1 increases hypersensitivity to painful stimuli and regulation of Kv2.1 protein expression through the epigenetic factor Cdyl modulates neuronal excitability and nociception (Sun et al, 2022). Consistent with these studies, our results show that Kv2 channels are localized to DRG neuron axons, where they could potentially influence electrical transmission.…”

“…The subcellular localization of voltage-gated ion channels in neurons determines how electrical signals are propagated. The two members of the Kv2 family of voltage gated potassium channels, Kv2.1 and Kv2.2, are important for modulating electrical signals in mammalian somatosensory neurons (Bocksteins et al, 2009; Lee et al, 2020; Sun et al, 2022; Tsantoulas et al, 2014; Zheng et al, 2019), yet little is known about where Kv2 channels are localized in these neurons. In central neurons, Kv2 channels are sequestered to specific subcellular regions and identification of where these channels are has helped elucidate their functional roles (Bishop et al, 2015; Du, Tao-Cheng, Zerfas, & McBain, 1998; Irie, 2021; Jensen et al, 2017; Johnson et al, 2018; Kihira, Hermanstyne, & Misonou, 2010; Kirmiz, Vierra, Palacio, & Trimmer, 2018; Misonou, Mohapatra, Menegola, & Trimmer, 2005; Muennich & Fyffe, 2004; Romer et al, 2014; Scannevin, Murakoshi, Rhodes, & Trimmer, 1996; Trimmer, 1991; Vierra, O’Dwyer, Matsumoto, Santana, & Trimmer, 2021).…”

“…Kv2.1 and Kv2.2 mRNA transcript levels are decreased after peripheral axotomy of rat DRG neurons (Tsantoulas et al, 2014). Suppression of Kv2.1 transcription by the epigenetic factor Cdyl is implicated in regulating pain sensation (Sun et al, 2022). A missing piece of the puzzle of how Kv2 channels are involved in somatosensory neuron function is the location of the channels themselves.…”

Global research trends on epigenetics and neuropathic pain: A bibliometric analysis

“…Recent studies have demonstrated that the relevant underlying mechanisms of NP are related to epigenetic modifications ( Frances et al, 2022 ; Jiang et al, 2022 ). The epigenetic regulator plays a crucial role in the maintenance and development of NP by activating and suppressing various gene expressions, such as neuroinflammatory factors, neurotransmitters, receptors, and ion channels ( Franco-Enzastiga et al, 2021 ; Borgonetti et al, 2022 ; Sun et al, 2022 ; Zhang J. et al, 2022 ). Given that the publication of epigenetics and NP is rapidly evolving, understanding the research progress, trends, and hotspots in this field is necessary for relevant researchers.…”