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

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.

Compartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α

“…Recently, we developed high-fidelity molecular tools and live-imaging methodology that enable the study of ion channel regulation at these distal sites. 8 , 9 , 50 , 51 We used this approach to further elucidate the spatiotemporal mechanisms underlying the regulation of Na V 1.7 by TNF-α.…”

“…Using tagged full-length Na V channel constructs coupled with spinning-disk confocal microscopy, it is now possible to evaluate the effects of inflammatory mediators on these channels in both somas and distal axons of sensory neurons. 8 , 9 , 37 Together with electrophysiological recordings, these techniques allow us to study the effects of TNF-α on the biophysical properties of Na V 1.7, as well as the temporal and spatial regulation of channel insertion at the plasma membrane of somas and axons of sensory neurons.…”

Schwann cells promote sensory neuron excitability during development

“…Of the putative prostaglandins detected in SCCM, prostaglandin E 2 (PGE 2 ) is a signaling molecule with diverse functions in development, repair, and inflammation 43–48 . Intriguingly, PGE 2 has been shown to affect several aspects of Na V function in mature sensory neurons, including ion conduction, phosphorylation, trafficking, and expression 49–58 . This established role of PGE 2 in neuronal excitability led us to hypothesize that PGE 2 is the excitability-inducing molecule in Schwann cell-conditioned media.…”

Synergistic interaction and activation of the opioid receptor-NO–cGMP–K+ channel pathway on peripheral antinociception induced by the α-Bisabolol-diclofenac combination

“…Our results suggest the presence, in subcutaneous tissue nociceptors, of ATP-sensitive-, Ca 2+ -activated- and voltage-gated K + channels that are activated or controlled by cGMP. Due to the K + gradient (produced by the Na + /K + -ATPase), the opening of the K + channel results in an abrupt outward release of K + , causing hyperpolarization ( Higerd-Rusli et al, 2023 ). In this sense, hyperpolarization desensitizes the neuron and prevents it from being activated or depolarized by another stimulus during this time, or at least raises the threshold for any new stimulus ( Higerd-Rusli et al, 2023 ).…”

“…Due to the K + gradient (produced by the Na + /K + -ATPase), the opening of the K + channel results in an abrupt outward release of K + , causing hyperpolarization ( Higerd-Rusli et al, 2023 ). In this sense, hyperpolarization desensitizes the neuron and prevents it from being activated or depolarized by another stimulus during this time, or at least raises the threshold for any new stimulus ( Higerd-Rusli et al, 2023 ). Thus, hyperpolarization prevents depolarizations from occurring, thus avoiding the transmission and conduction of messages to second or third order neurons.…”