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Papers of the Week

Papers: 17 Dec 2022 - 23 Dec 2022

2022 Dec 17

J Biol Chem

The fates of internalized Na1.7 channels in sensory neurons: retrograde co-transport with other ion channels, axon-specific recycling, and degradation.


Higerd-Rusli GP, Tyagi S, Liu S, Dib-Hajj FB, Waxman SG, Dib-Hajj SD
J Biol Chem. 2022 Dec 17:102816.
PMID: 36539035.


Neuronal function relies on the maintenance of appropriate levels of various ion channels at the cell membrane, which is accomplished by balancing secretory, degradative, and recycling pathways. Neuronal function further depends on membrane specialization through polarized distribution of specific proteins to distinct neuronal compartments such as axons. Voltage-gated sodium channel Na1.7, a threshold channel for firing action potentials in nociceptors, plays a major role in human pain, and its abundance in the plasma membrane is tightly regulated. We have recently characterized the anterograde axonal trafficking of Na1.7 channels in Rab6A-positive vesicles, but the fate of internalized channels is not known. Membrane proteins which have undergone endocytosis can be directed into multiple pathways including those for degradation, recycling to the membrane, and transcytosis. Here we demonstrate Na1.7 endocytosis and dynein-dependent retrograde trafficking in Rab7-containing late endosomes together with other axonal membrane proteins using real-time imaging of live neurons. We show that some internalized Na1.7 channels are delivered to lysosomes within the cell body, and that there is no evidence for Na1.7 transcytosis. In addition, we show that Na1.7 is recycled specifically to the axonal membrane as opposed to the soma membrane, suggesting a novel mechanism for the development of neuronal polarity. Together, these results shed light on the mechanisms by which neurons maintain excitable membranes and may inform efforts to target ion channel trafficking for the treatment of disorders of excitability.