Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity

Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degra-dation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel NaV1.7 and potassium channel KV7.2 promote and oppose excitability in nocice-ptors, respectively. We used live-cell imaging to investigate mechanisms by which inflam-matory mediators (IM) modulate the abundance of these channels at axonal surfaces through transcription, vesicular loading, axonal transport, exocytosis, and endocytosis. Inflammatory mediators induced a NaV1.7-dependent increase in activity in distal axons. Further, inflammation increased the abundance of NaV1.7, but not of KV7.2, at axonal surfaces by selectively increasing channel loading into anterograde transport vesicles and insertion at the membrane, without affecting retrograde transport. These results uncover a cell biological mechanism for inflammatory pain and suggest NaV1.7 trafficking as a potential therapeutic target.

Automated summary

Inflammation causes pain by altering the ionic currents in nociceptors, resulting in increased excitability. NaV1.7 and KV7.2 channels play opposing roles in nociceptor excitability. This study used live-cell imaging to investigate the mechanisms by which inflammatory mediators regulate the abundance of these channels at axonal surfaces. The results revealed a cell biological mechanism for inflammatory pain and suggested NaV1.7 trafficking as a potential therapeutic target.