Building sensory axons: Delivery and distribution of Na(V)1.7 channels and effects of inflammatory mediators

Sodium channel Na(V)1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies. However, little is known about Na(V)1.7 trafficking or membrane distribution along sensory axons, which can be a meter or more in length. We show here with single-molecule resolution the first live visualization of Na(V)1.7 channels in dorsal root ganglia neurons, including long-distance microtubule-dependent vesicular transport in Rab6A-containing vesicles. We demonstrate nanoclusters that contain a median of 12.5 channels at the plasma membrane on axon termini. We also demonstrate that inflammatory mediators trigger an increase in the number of Na(V)1.7-carrying vesicles per axon, a threefold increase in the median number of Na(V)1.7 channels per vesicle and a ~50% increase in forward velocity. This remarkable enhancement of Na(V)1.7 vesicular trafficking and surface delivery under conditions that mimic a disease state provides new insights into the contribution of Na(V)1.7 to inflammatory pain.