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Modulation of sensory neuron excitability by functionally altered NaV1.9 channels

Subject Area Molecular Biology and Physiology of Neurons and Glial Cells
Anatomy and Physiology
Biochemistry
Term from 2014 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 263323902
 
Final Report Year 2024

Final Report Abstract

Voltage-gated sodium channels (NaV channels) play a key role in the electrical signaling of nociceptive afferents, as they initiate action potentials that transmit the information to the central nervous system. The three channel subtypes NaV1.7, NaV1.8 and NaV1.9 show the highest expression levels in nociceptive neurons and are therefore of particular importance in these cells. Consequently, gene mutations affecting the function of these channels are associated with a whole spectrum of human pain disorders. For example, while increased activity of NaV1.7 and NaV1.8 can cause neuropathic pain syndromes, loss-of-function of NaV1.7 is associated with congenital analgesia. However, among this group, C-fiber-specific NaV1.9 channels appear to be unique, as gain-of-function variants are paradoxically linked to both neuropathic pain and congenital analgesia. In addition, NaV1.9-dependent analgesia is accompanied by severe intestinal dysfunction, indicating a role of the channels in enteric neurons. The project aimed to identify functional alterations of pathogenic NaV1.9 variants that correlate with the clinical picture of pain insufficiency and those that are associated with neuropathic pain. Since heterologous expression of NaV1.9 in immortalized neuronal host cells is notoriously difficult, we instead used neurons isolated from dorsal root ganglia of NaV1.8/NaV1.9-deficient mice (DKO-DRG-neurons) generated in the framework of the project. These cells proved to be an ideal tool for systematic structure-function analyses of human NaV1.9 channels. Quantitative electrophysiological analysis of known and newly identified pathogenic NaV1.9 variants revealed that pain-associated variants are characterized by either enhanced activation or defective inactivation, whereas the variants associated with pain insufficiency show both functional alterations. The data suggest that NaV1.9-dependent analgesia is likely the consequence of a combination of enhanced activation and impaired inactivation of the channels. To study pathogenic channel variants also in the context of enteric neurons, we established a method for the isolation and subsequent transfection of neurons from the myenteric plexus of mice facilitating the functional analysis of channel variants in this disease-relevant background. In summary, the project demonstrates the importance of NaV1.9 channels for human pain physiology and identifies disease-specific malfunctions characterizing channel variants associated with the clinical picture of congenital analgesia or neuropathic pain syndromes.

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