Hierarchical CRMP2 posttranslational modifications control NaV1.7 function

Erik T. Dustrude, Aubin Moutal, Xiaofang Yang, Yuying Wang, May Khanna, Rajesh Khanna

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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 clathrindependent 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.

Original languageEnglish (US)
Pages (from-to)E8443-E8452
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number52
DOIs
StatePublished - Dec 27 2016

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Post Translational Protein Processing
Sumoylation
Phosphorylation
Ubiquitin
NAV1.7 Voltage-Gated Sodium Channel
Cyclin-Dependent Kinase 5
Voltage-Gated Sodium Channels
collapsin response mediator protein-2
Ubiquitin-Protein Ligases
Neuralgia
Endocytosis
Epidermal Growth Factor Receptor
Proteins
Membranes

Keywords

  • CRMP2
  • NaV1.7 sodium channel
  • Phosphorylation
  • SUMOylation
  • Trafficking

ASJC Scopus subject areas

  • General

Cite this

Hierarchical CRMP2 posttranslational modifications control NaV1.7 function. / Dustrude, Erik T.; Moutal, Aubin; Yang, Xiaofang; Wang, Yuying; Khanna, May; Khanna, Rajesh.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 52, 27.12.2016, p. E8443-E8452.

Research output: Contribution to journalArticle

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