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.

 抽象的

离子通道是所有形式的电信号的基础，包括有害事件信息的传输。电压门控钙离子通道具有双重功能，它们支持电信号传导以及通过兴奋依赖性钙跨质膜进入的细胞内钙信号传导。调节离子通道形式和作用的机制对于无数细胞功能至关重要，这些是药物和治疗的目标。当控制离子通道活性的细胞机制被破坏时，可能会导致疾病的病理生理学。例如，选择性前 mRNA 剪接是定义从早期细胞分化到程序性细胞凋亡的不同细胞类型的转录组精确组成的一个重要步骤。据估计，30% 的致病突变与选择性剪接的改变有关，而错误剪接是许多高度流行的疾病的一个特征，包括神经退行性疾病、癌症和慢性疼痛。在这里，我们讨论了基因表达的表观遗传调控和伤害感受器中钙离子通道的细胞特异性选择性剪接的重要作用，重点是这些过程在慢性疼痛中如何被破坏，纠正或补偿异常离子通道剪接的潜在治疗益处在慢性疼痛中。