Building sensory axons: Delivery and distribution of Na_V1.7 channels and effects of inflammatory mediators.

Abstract

Sodium channel Na_V1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies. However, little is known about Na_V1.7 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_V1.7 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_V1.7-carrying vesicles per axon, a threefold increase in the median number of Na_V1.7 channels per vesicle and a ~50% increase in forward velocity. This remarkable enhancement of Na_V1.7 vesicular trafficking and surface delivery under conditions that mimic a disease state provides new insights into the contribution of Na_V1.7 to inflammatory pain.