Ion channel modulators to treat itch
Even though the scientific community is in virtual agreement on a prominent contribution of Nav1.9 (gene name: SCN11A) to pain, the role of this voltage-gated sodium (Nav) channel subtype in itch (pruritis) is unknown. Yet, patients with a heterozygous Nav1.9 p.L811P mutation consistently report debilitating pruritis. Using a combination of techniques, we found that Nav1.9 is expressed in a subset of non-myelinated, non-peptidergic small-diameter dorsal root ganglion cells (DRGs). In wild-type DRGs, but not those of Nav1.9 knockout mice, itch-evoking agents altered action potential parameters and Nav channel gating properties. Additionally, Nav1.9 knockout mice exhibited a strong reduction in acute scratching behavior in response to pruritogens, whereas mice expressing the human Nav1.9 p.L811P variant displayed increased spontaneous scratching. Combined, these results illustrate a key role for Nav1.9 in itch and lay the foundation for this project in which we will establish a much-needed pharmacological profile of this channel. Our efforts will help identify drugs capable of tackling the clinical problem of chronic itch and drastically expand our understanding of its pathophysiological underpinnings. To achieve these goals, we put together an international consortium consisting of functional, structural, and pharmacological experts with all the required tools to carry out our objectives.
Pharmacology, Electrophisiological approaches, Behavioural methodologies, Animal studies, chronic itch, cryo-em structure, sodium channel
2021 - 2024
Bosmans Frank (Coordinator)
Michel De Waard
Filip Van Petegem