BPS2026 – Biophysical characterization of the Nav1.9 Na+ channel in human sensory neurons

In human dorsal root ganglia (DRG), and trigeminal (TG) neurons, the tetrodotoxin (TTX)-sensitive, and -resistant voltage-gated sodium channels (Na V ) play critical roles in the firing of action potentials, which drive electrical impulses to facilitate many downstream processes such as sensory perception, itch, and pain. Particularly, the inhibition of Na V 1.7 and/or Na V 1.8 through pharmacology and naturally occurring channel-inactivating mutations, present in human individuals with congenital pain-insensitivity, has been shown to reduce and eliminate pain sensitivity. Therefore, both channels are considered ideal drug targets for analgesia. However, thus far only Na V 1.8 has been fully validated for human analgesia by pharmacological means, and it is the target for the recently approved new analgesic Suzetrigine. A second TTX-resistant channel, Na V 1.9, is also abundantly expressed in both DRG and TG neurons. Na V 1.9 channels exhibit distinct biophysical properties with a slower onset of activation and even slower inactivation than Na V 1.8 which results in a persistent background current that is thought to modulate resting membrane potential and cellular excitability. Gain-of-function mutations in Na V 1.9 lead to familial episodic pain syndrome, suggesting that it may be a promising target for the treatment of pain. While most studies have been conducted in rodent and heterologous expression models, the unique gating characteristics, and pharmacology in human primary neurons are still largely unknown. Here, we pharmacologically isolated and recorded Na V 1.9 currents in both human DRG and TG neurons and compared their biophysical properties. We found several differences—Na V 1.9 channels in TG neurons have a right-shifted G-V of inactivation, larger window current, and faster activation kinetics. The totality of these human primary neuron data provides further insight into the properties and regulation of Na V 1.9 channels and will provide important insights for future drug discovery efforts aimed at developing novel analgesics.