Epigenetic control of ion channel expression and cell-specific splicing in nociceptors: Chronic pain mechanisms and potential therapeutic targets

Abstract

Ion channels underlie all forms for electrical signaling including the transmission of information about harmful events. Voltage-gated calcium ion channels have dual function, they support electrical signaling as well as intracellular calcium signaling through excitation-dependent calcium entry across the plasma membrane. Mechanisms that regulate ion channel forms and actions are essential for myriad cell functions and these are targeted by drugs and therapeutics. When disrupted, the cellular mechanisms that control ion channel activity can contribute to disease pathophysiology. For example, alternative pre-mRNA splicing is a major step in defining the precise composition of the transcriptome across different cell types from early cellular differentiation to programmed apoptosis. An estimated 30% of disease-causing mutations are associated with altered alternative splicing, and mis-splicing is a feature of numerous highly prevalent diseases including neurodegenerative, cancer, and chronic pain. Here we discuss the important role of epigenetic regulation of gene expression and cell-specific alternative splicing of calcium ion channels in nociceptors, with emphasis on how these processes are disrupted in chronic pain, the potential therapeutic benefit of correcting or compensating for aberrant ion channel splicing in chronic pain.

Ion channels and pain in Fabry disease

“…Altered channel mRNA transcript levels, altered expression of the channel proteins, changes in their functional activity, in the cell bodies of sensory or CNS neurons, as well as alteration in channel trafficking in damaged nerves, seem to be key factors in pathological pain states. [93][94][95][96] For example, the calcium channel accessory subunit a2d1 is upregulated 20-fold in damaged peripheral neurons and is the site of action of the analgesic drugs gabapentin and pregabalin. 96 This subunit facilitates trafficking of Ca V 2.1 channels to the cell membrane, thus the analgesic action of gabapentin in patients with neuropathic pain could relate to the lowered calcium currents.…”

Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates Paclitaxel-Induced Neuropathic Pain

“…15 Epigenetic methylation of lysine on histone H3 proteins controlling transient receptor potential vanilloid subtype-1 (TRPV1) contributes to neuropathic pain. 16 Interestingly, PTX induces a stronger apoptotic effect on ovarian cancers by mediating the JMJD3/H3K27me3 signaling, 17 and neuropathic pain by upregulating the expression of TRPV1 in the DRG. 18 These data indicate that JMJD3/H3K27me3/ TRPV1 signaling plays as a regulator for PTX therapeutic approaches.…”

Regulation of N-type calcium channels by nociceptin receptors and its possible role in neurological disorders

“…In contrast, Cavβ subunits are cytoplasmic and attach to the Cavα 1 subunit at the linker between transmembrane domains I and II. With additional diversity arising from alternative splicing events, the existence of multiple ancillary subunits gives rise to a wide range of different calcium channel complexes [ 16 , 17 ]. The cryo-EM structure of Cav2.2 (and other) calcium channels has been solved [ 18 – 21 ] and has provided insights into the structural basis of channels function and pharmacology.…”