Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity
Grant P. Higerd‐Rusli, Sidharth Tyagi, Christopher A. Baker, Shujun Liu, Fadia B. Dib-Hajj, Sulayman D. Dib‐Hajj, Stephen G. Waxman
Abstract
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 degradation. Thus, alterations in ion channel trafficking may influence excitability. Sodium channel Na V 1.7 and potassium channel K V 7.2 promote and oppose excitability in nociceptors, respectively. We used live-cell imaging to investigate mechanisms by which inflammatory mediators (IM) modulate the abundance of these channels at axonal surfaces through transcription, vesicular loading, axonal transport, exocytosis, and endocytosis. Inflammatory mediators induced a Na V 1.7-dependent increase in activity in distal axons. Further, inflammation increased the abundance of Na V 1.7, but not of K V 7.2, 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 Na V 1.7 trafficking as a potential therapeutic target.