Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity.
Grant P HigerdSidharth TyagiChristopher A BakerShujun LiuFadia B Dib-HajjSulayman D Dib-HajjStephen G WaxmanPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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.
Keyphrases
- oxidative stress
- spinal cord injury
- diabetic rats
- chronic pain
- neuropathic pain
- pain management
- high resolution
- transcranial direct current stimulation
- magnetic resonance imaging
- computed tomography
- machine learning
- minimally invasive
- magnetic resonance
- antibiotic resistance genes
- transcription factor
- endothelial cells
- ionic liquid
- cystic fibrosis
- staphylococcus aureus
- mesenchymal stem cells
- mass spectrometry
- high glucose
- optic nerve
- fluorescence imaging
- deep learning