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bioRxiv · 10.1101/2020.09.29.318774

Studies on CRMP2 SUMOylation-deficient transgenic mice reveal novel insights into the trafficking of NaV1.7 channels

Gomez, K.·Ran, D.·Madura, C. L.·Moutal, A.·Khanna, R.
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Abstract

Voltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel NaV1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). If not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of NaV1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2K374A/K374A) female mice have reduced NaV1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2K374A/K374A female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male and female CRMP2K374A/K374A mice, increased pain sensitivity in allodynia-resistant animals. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2K374A/K374A mice. Finally, silencing these proteins in DRG neurons from female CRMP2K374A/K374A mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non SUMOylated CRMP2-mediated internalization of sodium channels in vivo.

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Gomez, K., Ran, D., Madura, C. L., Moutal, A., Khanna, R.. 2020-09-30. Studies on CRMP2 SUMOylation-deficient transgenic mice reveal novel insights into the trafficking of NaV1.7 channels. https://doi.org/10.1101/2020.09.29.318774

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