Electric currents in disc health: The role of ion channels in intervertebral disc pathophysiology.

Intervertebral disc degeneration (IVDD), which is known as a common global health concern, has been a significant factor in neck and back pain. The intervertebral discs are avascular structures consisting of the nucleus pulposus, annulus fibrosus, and cartilage endplate, which are crucial for regulating the spinal motion, withstanding stress, and buffering vibration. Due to their special anatomical structure and functional role, they are highly susceptible to stimulation by external factors. Ion channels are transmembrane proteins which have attracted significant attention and great progress in cardiovascular diseases and neurological diseases, and the importance of them in the pathophysiology of IVDD is gaining recognition. They function as a receptor to stimulate the influx of calcium within cells, which acts as a second messenger to activate downstream pathways and upregulate the expression of transcriptional protein, thereby triggering IVDD. This review classified the ion channel families into three types based on their primary activation mechanisms, and then described the regulation of ion channels from transcription and translation to trafficking and expression. Subsequently, the function of ion channels in the pathophysiology of IVDD as well as their potential and practicality in treatment were the main topics of this review. We hope this review could help understand and develop new, specific therapies for IVDD. The translational potential of this article: Targeted therapeutic strategies for ion channels are particularly critical in the treatment of IVDD. Ion channel-targeted drugs and tissue engineering strategies for ion channels have emerged as novel therapeutic targets for intervening in IVDD by modulating calcium homeostasis, inflammatory responses, and extracellular matrix metabolism in disc cells. In addition, as the development of nanotechnology, the integration of ion channel-targeted therapies with advanced drug delivery systems represents a promising frontier in the treatment of IVDD. Nanoparticle-based carriers and hydrogel-mediated sustained-release platforms have emerged as complementary strategies to enhance drug bioavailability and spatiotemporal control within the avascular, mechanically stressed intervertebral disc microenvironment. Furthermore, systematic exploration of combination therapies integrating ion channel-targeted drugs with complementary pharmacological agents like anti-inflammatory drugs and growth factors warrants rigorous investigation to enhance therapeutic efficacy in IVDD management.