Sodium Channels

Lampert, Angelika; Stühmer, Walter; Waxman, Stephen G.

doi:10.1002/9780470015902.a0000127.pub2

Cited by 2 publications

(2 citation statements)

References 43 publications

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“…Our voltage-clamp experiments, as well as our 3D computational modeling results for the N1245S variant do not directly support their pathogenicity. IEM is classically associated with a shift of voltagedependence of activation of Nav1.7 to more hyperpolarized potentials [26]. In some cases, alterations in other biophysical properties were reported, which is the reason for our in-depth analysis of the presented variants.…”

Section: Discussionmentioning

confidence: 90%

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Assessing the impact of pain-linked Nav1.7 variants: An example of two variants with no biophysical effect

et al. 2021

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Mutations in the voltage-gated sodium channel Nav1.7 are linked to human pain. The Nav1.7/N1245S variant was described before in several patients suffering from primary erythromelalgia and/or olfactory hypersensitivity. We have identified this variant in a pain patient and a patient suffering from severe and life-threatening orthostatic hypotension. In addition, we report a female patient suffering from muscle pain and carrying the Nav1.7/E1139K variant. We tested both Nav1.7 variants by whole-cell voltage-clamp recordings in HEK293 cells, revealing a slightly enhanced current density for the N1245S variant when co-expressed with the β1 subunit. This effect was counteracted by an enhanced slow inactivation. Both variants showed similar voltage dependence of activation and steady-state fast inactivation, as well as kinetics of fast inactivation, deactivation, and use-dependency compared to WT Nav1.7. Finally, homology modeling revealed that the N1245S substitution results in different intramolecular interaction partners. Taken together, these experiments do not point to a clear pathogenic effect of either the N1245S or E1139K variant and suggest they may not be solely responsible for the patients’ pain symptoms. As discussed previously for other variants, investigations in heterologous expression systems may not sufficiently mimic the pathophysiological situation in pain patients, and single nucleotide variants in other genes or modulatory proteins are necessary for these specific variants to show their effect. Our findings stress that biophysical investigations of ion channel mutations need to be evaluated with care and should preferably be supplemented with studies investigating the mutations in their context, ideally in human sensory neurons.

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Section: Discussionmentioning

confidence: 90%

“…IEM is classically associated with a shift of voltage-dependence of activation of Nav1.7 to more hyperpolarized potentials [ 26 ]. In some cases, alterations in other biophysical properties were reported, which is the reason for our in-depth analysis of the presented variants.…”

Section: Discussionmentioning

confidence: 99%

Assessing the impact of pain-linked Nav1.7 variants: An example of two variants with no biophysical effect

et al. 2021

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Genetics meets function in sodium channel-related pain disorders

et al. 2022

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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.

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Sodium Channels

Cited by 2 publications

References 43 publications

Assessing the impact of pain-linked Nav1.7 variants: An example of two variants with no biophysical effect

Assessing the impact of pain-linked Nav1.7 variants: An example of two variants with no biophysical effect

Genetics meets function in sodium channel-related pain disorders

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