Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling. Trafficking of the voltage-gated sodium channel NaV1.7 is dysregulated in neuropathic pain. We identify a trafficking program for NaV1.7 driven by hierarchical interactions with posttranslationally modified versions of the binding partner collapsin response mediator protein 2 (CRMP2). The binding described between CRMP2 and NaV1.7 was enhanced by conjugation of CRMP2 with small ubiquitin-like modifier (SUMO) and further controlled by the phosphorylation status of CRMP2. We determined that CRMP2 SUMOylation is enhanced by prior phosphorylation by cyclin-dependent kinase 5 and antagonized by Fyn phosphorylation. As a consequence of CRMP2 loss of SUMOylation and binding to NaV1.7, the channel displays decreased membrane localization and current density, and reduces neuronal excitability. Preventing CRMP2 SUMOylation with a SUMO-impaired CRMP2-K374A mutant triggered NaV1.7 internalization in a clathrin-dependent manner involving the E3 ubiquitin ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4) and endocytosis adaptor proteins Numb and epidermal growth factor receptor pathway substrate 15. Collectively, our work shows that diverse modifications of CRMP2 cross-talk to control NaV1.7 activity and illustrate a general principle for regulation of NaV1.7.
Pubmed ID: 27940916 RIS Download
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This monoclonal targets β-Actin
View all literature mentionsThis unknown targets RAB11A
View all literature mentionsThis unknown targets RAB5
View all literature mentionsThis monoclonal targets Itch
View all literature mentionsThis monoclonal targets NEDD4-2 antibody [EPR8461]
View all literature mentionsThis monoclonal targets EPS15
View all literature mentionsThis polyclonal targets NUMB
View all literature mentionsThis unknown targets SUMO-1
View all literature mentionsThis polyclonal targets Rabbit Human CRMP2 phospho (Thr555)
View all literature mentionsThis polyclonal targets DPYSL2
View all literature mentionsThis polyclonal targets CRMP2 phospho Thr 509 + Thr 514
View all literature mentionsThis unknown targets CRMP2
View all literature mentionsThis monoclonal targets βIII Tubulin
View all literature mentionsThis unknown targets Pan NaV Channel
View all literature mentionsThis monoclonal targets Nav1.7 Na+ channel
View all literature mentionsCell line CAD is a Transformed cell line with a species of origin Mus musculus (Mouse)
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