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Hierarchical CRMP2 posttranslational modifications control NaV1.7 function.

Erik T Dustrude1, Aubin Moutal1, Xiaofang Yang1

  • 1Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85742.

Proceedings of the National Academy of Sciences of the United States of America
|December 13, 2016
PubMed
Summary

Post-translational modifications of collapsin response mediator protein 2 (CRMP2) control voltage-gated sodium channel NaV1.7 trafficking. CRMP2 SUMOylation and phosphorylation regulate NaV1.7 membrane localization and neuronal excitability, impacting neuropathic pain.

Keywords:
CRMP2NaV1.7 sodium channelSUMOylationphosphorylationtrafficking

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Channelopathies

Background:

  • Voltage-gated sodium channels, particularly NaV1.7, are critical for neuronal excitability and signaling.
  • Dysregulation of NaV1.7 trafficking is implicated in neuropathic pain pathogenesis.
  • Collapsin response mediator protein 2 (CRMP2) is a key binding partner for NaV1.7.

Purpose of the Study:

  • To elucidate the role of post-translational modifications of CRMP2 in regulating NaV1.7 trafficking and function.
  • To investigate the hierarchical interactions between CRMP2 modifications and NaV1.7 binding.
  • To understand the molecular mechanisms underlying NaV1.7 dysregulation in neuropathic pain.

Main Methods:

  • Investigated CRMP2 binding to NaV1.7 using techniques assessing SUMOylation and phosphorylation.
  • Utilized a SUMO-impaired CRMP2 mutant (CRMP2-K374A) to study NaV1.7 internalization.
  • Examined the involvement of clathrin-dependent endocytosis machinery, including Nedd4-2, Numb, and EPS15.

Main Results:

  • CRMP2 binding to NaV1.7 is modulated by SUMOylation and phosphorylation.
  • CRMP2 SUMOylation is positively regulated by cyclin-dependent kinase 5 phosphorylation and negatively by Fyn phosphorylation.
  • Loss of CRMP2 SUMOylation leads to reduced NaV1.7 membrane localization, decreased current density, and diminished neuronal excitability.
  • Preventing CRMP2 SUMOylation induces NaV1.7 internalization via clathrin-dependent endocytosis involving Nedd4-2, Numb, and EPS15.

Conclusions:

  • Diverse post-translational modifications of CRMP2 exhibit cross-talk to precisely control NaV1.7 channel activity.
  • This study reveals a fundamental mechanism for regulating NaV1.7 channel trafficking and function.
  • Understanding these regulatory pathways offers potential therapeutic targets for neuropathic pain.