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

Sodium channel Na1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies. However, little is known about Na1.7 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 Na1.7 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 Na1.7-carrying vesicles per axon, a threefold increase in the median number of Na1.7 channels per vesicle and a ~50% increase in forward velocity. This remarkable enhancement of Na1.7 vesicular trafficking and surface delivery under conditions that mimic a disease state provides new insights into the contribution of Na1.7 to inflammatory pain.