Genetics meets function in sodium channel-related pain disorders

Abstract

Voltage-gated sodium channels are crucial for pain perception. This is illustrated by several human genetic conditions that lead to either chronic pain or, vice versa, to congenital painlessness. The type of mutation, its impact on neuron excitability as well as the affected sodium channel subtype delineates a complex picture of the disorders. Genetic variants in sodium channels may affect the complex biophysical gating and also their trafficking, association with other proteins and more complex regulations of the channel protein and function, thus allowing us to explore the subtle but impactful effects of their dysregulation for human nociception. A detailed understanding of these pain disorders provides a unique chance to understand the detailed intricacies of nociception and pathological conditions such as neuropathic pain. With increasing awareness of the importance of sodium channel variants in neuropathic pain, more patients are genetically screened, sometimes identifying variants of unclear significance (VUS). Bioinformatic tools help to assess their potential disease causing impact, but functional studies using patch-clamp experiments in cell lines are needed to allow for reliable conclusions. Often cell lines are not sufficient to show a physiologically relevant phenotype and more complex, time intensive models, such as induced pluripotent stem cells (iPS-cells) are employed. A challenge remains to identify the role of each sodium channel VUS in the context of the detailed cellular genetic and functional context. To lay the grounds for such a detailed interpretation, we need a correlation of cellular function and genetic transcription on a single cell basis, as it is possible with the Patch-Seq technique. The more detailed our knowledge becomes on functional and genetic sensory neurons subtypes and their role in the generation of neuropathic pain, the more targeted the personal or population-based treatment can be.

Sodium channels expressed in nociceptors contribute distinctly to action potential subthreshold phase, upstroke and shoulder

“…Alternative splicing, trafficking or membrane turnover are just some factors that may impact channel translation from RNA to functional protein in the membrane. A promising solution to these problems are single-cell transcriptomics, such as Patch-seq, which offer the ability to link expression data to cell physiology (Lipovsek et al 2021, Körner et al 2022). Furthermore, since expression data is gathered at the cell soma, only limited assumptions can be made for small nerve fibers, e.g., in the human skin.…”