Depolarizing NaV and Hyperpolarizing KV Channels Are Co-Trafficked in Sensory Neurons

• Published in: The Journal of neuroscience Vol. 42; no. 24; pp. 4794 - 4811
• Main Authors: Higerd-Rusli, Grant P, Alsaloum, Matthew, Tyagi, Sidharth, Sarveswaran, Nivedita, Estacion, Mark, Akin, Elizabeth J, Dib-Hajj, Fadia B, Liu, Shujun, Sosniak, Daniel, Zhao, Peng, Dib-Hajj, Sulayman D, Waxman, Stephen G
• Format: Journal Article
• Language: English
• Published: Baltimore Society for Neuroscience 15.06.2022
• Subjects: Axons; Depolarization; Epilepsy; Excitability; Ion channels; Isoforms; Membrane proteins; Membranes; Mutation; Na+/Ca2+ exchanger; Neurons; Packaging; Pain; Physiology; Potassium; Potassium channels (voltage-gated); Protein transport; Proteins; Sensory neurons; Sodium channels (voltage-gated); Tumor necrosis factor receptors; Vesicles
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.0058-22.2022

Neuronal excitability relies on coordinated action of functionally distinction channels. Voltage-gated sodium (NaV) and potassium (KV) channels have distinct but complementary roles in firing action potentials: NaV channels provide depolarizing current while KV channels provide hyperpolarizing current. Mutations and dysfunction of multiple NaV and KV channels underlie disorders of excitability, including pain and epilepsy. Modulating ion channel trafficking may offer a potential therapeutic strategy for these diseases. A fundamental question, however, is whether these channels with distinct functional roles are transported independently or packaged together in the same vesicles in sensory axons. We have used Optical Pulse-Chase Axonal Long-distance imaging to investigate trafficking of NaV and KV channels and other axonal proteins from distinct functional classes in live rodent sensory neurons (from male and female rats). We show that, similar to NaV1.7 channels, NaV1.8 and KV7.2 channels are transported in Rab6a-positive vesicles, and that each of the NaV channel isoforms expressed in healthy, mature sensory neurons (NaV1.6, NaV1.7, NaV1.8, and NaV1.9) is cotransported in the same vesicles. Further, we show that multiple axonal membrane proteins with different physiological functions (NaV1.7, KV7.2, and TNFR1) are cotransported in the same vesicles. However, vesicular packaging of axonal membrane proteins is not indiscriminate, since another axonal membrane protein (NCX2) is transported in separate vesicles. These results shed new light on the development and organization of sensory neuron membranes, revealing complex sorting of axonal proteins with diverse physiological functions into specific transport vesicles.